|
1
|
Gotchev D, Dorsey BD, Nguyen D, Kakarla R, Dugan B, Chen S, Gao M, Bailey L, Liu F, Harasym T, Chiu T, Tang S, Lee ACH, Cole AG, Sofia MJ. Structure-Activity Relationships and Discovery of ( S)-6-Isopropyl-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6 H-pyrido[1,2- h][1,7]naphthyridine-9-carboxylic Acid (AB-452), a Novel Orally Available HBV RNA Destabilizer. J Med Chem 2024; 67:1421-1446. [PMID: 38190324 DOI: 10.1021/acs.jmedchem.3c01981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments. Here we describe the identification of AB-452, a dihydroquinolizinone (DHQ) analogue. AB-452 is a potent HBV RNA destabilizer by inhibiting PAPD5/7 proteins in vitro with good in vivo efficacy in a chronic HBV mouse model. AB-452 showed acceptable tolerability in 28-day rat and dog toxicity studies, and a high degree of oral exposure in multiple species. Based on its in vitro and in vivo profiles, AB-452 was identified as a clinical development candidate.
Collapse
Affiliation(s)
- Dimitar Gotchev
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Bruce D Dorsey
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Duyan Nguyen
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Ramesh Kakarla
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Benjamin Dugan
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Shuai Chen
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Min Gao
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Laurèn Bailey
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Fei Liu
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Troy Harasym
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Tim Chiu
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Sunny Tang
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Amy C-H Lee
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Andrew G Cole
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Michael J Sofia
- Arbutus Biopharma, 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| |
Collapse
|
|
2
|
Zhao Q, Liu H, Tang L, Wang F, Tolufashe G, Chang J, Guo JT. Mechanism of interferon alpha therapy for chronic hepatitis B and potential approaches to improve its therapeutic efficacy. Antiviral Res 2024; 221:105782. [PMID: 38110058 DOI: 10.1016/j.antiviral.2023.105782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Hepatitis B virus (HBV) chronically infects 296 million people worldwide and causes more than 820,000 deaths annually due to cirrhosis and hepatocellular carcinoma. Current standard-of-care medications for chronic hepatitis B (CHB) include nucleos(t)ide analogue (NA) viral DNA polymerase inhibitors and pegylated interferon alpha (PEG-IFN-α). NAs can efficiently suppress viral replication and improve liver pathology, but not eliminate or inactivate HBV covalently closed circular DNA (cccDNA). CCC DNA is the most stable HBV replication intermediate that exists as a minichromosome in the nucleus of infected hepatocyte to transcribe viral RNA and support viral protein translation and genome replication. Consequentially, a finite duration of NA therapy rarely achieves a sustained off-treatment suppression of viral replication and life-long NA treatment is most likely required. On the contrary, PEG-IFN-α has the benefit of finite treatment duration and achieves HBsAg seroclearance, the indication of durable immune control of HBV replication and functional cure of CHB, in approximately 5% of treated patients. However, the low antiviral efficacy and poor tolerability limit its use. Understanding how IFN-α suppresses HBV replication and regulates antiviral immune responses will help rational optimization of IFN therapy and development of novel immune modulators to improve the rate of functional cure. This review article highlights mechanistic insight on IFN control of HBV infection and recent progress in development of novel IFN regimens, small molecule IFN mimetics and combination therapy of PEG-IFN-α with new direct-acting antivirals and therapeutic vaccines to facilitate the functional cure of CHB.
Collapse
Affiliation(s)
- Qiong Zhao
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Hui Liu
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Liudi Tang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Fuxuan Wang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | | | - Jinhong Chang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, United States.
| |
Collapse
|
|
3
|
Kawanaka M, Nishino K, Kawamoto H, Haruma K. Hepatitis B: Who should be treated?-managing patients with chronic hepatitis B during the immune-tolerant and immunoactive phases. World J Gastroenterol 2021; 27:7497-7508. [PMID: 34887645 PMCID: PMC8613739 DOI: 10.3748/wjg.v27.i43.7497] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/31/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
New hepatitis B virus (HBV) infections are decreasing owing to improved antiviral therapy and increased HBV vaccination worldwide; however, the number of HBV infections remains a major cause of liver carcinogenesis. HBV triggers cytotoxic immunity to eliminate HBV-infected cells. Therefore, the HBV pathophysiology changes in persistently infected individuals depending on host immune responses and HBV DNA proliferation state. To prevent liver cirrhosis and carcinogenesis caused by HBV, it is important to treat HBV infection at an early stage. Active treatment is recommended for the immunoactive hepatitis B surface-antigen-positive and -negative phase, but not during the immune-inactive phase or immune-tolerant phase; instead, follow-up is recommended. However, these patients should be monitored through regular blood tests to accurately diagnose the immune-inactive or -tolerant phases. The treatment regimen should be determined based on the age, sex, family history of liver cancer, and liver fibrosis status of patients. Early treatment is often recommended due to various problems during the immune-tolerant phase. This review compares the four major international practice guidelines, including those from the Japanese Society of Hepatology, and discusses strategies for chronic hepatitis B treatment during the immune-tolerant, immune-inactive, and resolved phases. Finally, recommended hepatitis B antiviral therapy and follow-up protocols are discussed.
Collapse
Affiliation(s)
- Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Ken Nishino
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Ken Haruma
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| |
Collapse
|
|
4
|
Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
| | | |
Collapse
|
|
5
|
Kang L, Pian Y, Gao Z, Hu J, Nie J. The influence of hepatitis B virus infection in pregnant women. Health Care Women Int 2021; 42:251-260. [PMID: 33724163 DOI: 10.1080/07399332.2021.1883024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We carried out the investigation to evaluate hepatitis B virus (HBV) infection status and the influence of HBV infection in pregnant women in Tianjin of China. We founded that the prevalence of HBsAg was 3.77% (69/1829). 88.57% (1620/1829) pregnant women conducted HBsAg screening in last pregnancy. Spontaneous abortion and premature delivery did not show significant differences between HBV infected and uninfected pregnant women. But ALT and AST levels were significantly higher in infected women. And 56.65% of participants (997/1760) were anti-HBs positive. In conclusion, HBsAg prevalence was moderate in pregnant women in this region, which was consistent with the total population in western Pacific regions. And HBV infection did not influence spontaneous abortion and premature delivery. But the HBsAg screening was conducted mostly in the last pregnancy. Early screening and intervention were suggested in pregnant women within countries of moderately endemic regions.
Collapse
Affiliation(s)
- Lina Kang
- Department of Clinical Laboratory, Tianjin Binhai New Area Dagang Hospital, Tianjin, China
| | - Yaya Pian
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhenxiang Gao
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jihong Hu
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingjing Nie
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
6
|
Komatsu H, Inui A, Yoshio S, Fujisawa T. Pharmacotherapy options for managing hepatitis B in children. Expert Opin Pharmacother 2021; 22:449-467. [PMID: 33090882 DOI: 10.1080/14656566.2020.1841165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION To eliminate viral hepatitis by 2030, the World Health Organization (WHO) launched the first global health sector strategy on viral hepatitis, with particular focus given to hepatitis B and C in 2016. To achieve the reduction of mortality in children, it is indispensable to know which children should be treated and how to treat them. AREA COVERED In this article, the authors review the antiviral treatment of children with chronic hepatitis B virus (HBV) infection including antivirals available for children with chronic HBV infection. EXPERT OPINION The approvals of nucleos(t)ide analogues (NAs) and pegylated interferon (PEG-IFN) for children have lowered a hurdle to the initiation of antiviral treatment in children. The international guidelines use nearly the same criteria of antiviral treatment for children with chronic HBV infection, but the WHO guidelines provide a cautious stance on the antiviral treatment of children. Not only PEG-IFN but also NAs with a high genetic barrier to drug resistance should be the first-line treatment for children. In settings with limited medical resources, NAs can be the first-line treatment for children. Although the concept of an 'immune-tolerant phase' is challenged, evidence is not sufficient to recommend the treatment of HBeAg-positive immune-tolerant children.
Collapse
Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Sachiyo Yoshio
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| |
Collapse
|
|
7
|
Jeng WJ, Lok ASF. Is Cure of Hepatitis B Infection a Mission Possible? HEPATITIS B VIRUS AND LIVER DISEASE 2021:475-495. [DOI: 10.1007/978-981-16-3615-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
8
|
Clemente MG, Antonucci R, Sotgiu G, Dettori M, Piana A, Vajro P. Present and future management of viral hepatitis B and C in children. Clin Res Hepatol Gastroenterol 2020; 44:801-809. [PMID: 32173307 DOI: 10.1016/j.clinre.2020.02.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 01/19/2020] [Accepted: 02/07/2020] [Indexed: 02/07/2023]
Abstract
Having a hepatitis B virus (HBV) or hepatitis C virus (HCV) infection places a child at higher risk for subsequent chronic hepatitis B (CHB) or chronic hepatitis C (CHC) infection. The risk of mother-to-child transmission is higher for HBV (20% to 90%) than for HCV (<5%). Perinatal HBV infection generally causes CHB infection while perinatal HCV infection has a certain rate of spontaneous viral clearance (around 20% to 30%). Of the two, only HBV infection can benefit from passive/active perinatal immunoprophylaxis. The risk of CHB in children with HBV horizontal transmission decreases with age, whereas HCV transmission among teenagers commonly results into a long-life infection and CHC infection. Children with CHB or CHC should be carefully assessed for the need for antiviral treatment. When treatment cannot be deferred, pediatric CHB infection has different first-line treatment options: standard interferon (for children aged≥1 year), pegylated interferon (for children aged≥3 years), and the oral nucleotide analogues entecavir (for children aged≥2 years) and tenofovir (for children aged≥12 years). The choice of treatment depends on the child's age, virus genotypes, previous treatment failure and presence of contraindications. Expected responsiveness rate is 25% of hepatitis B e-antigen clearance, with both standard interferon and nucleotide analogues. Direct antiviral agents are first-line treatment for CHC infection in children aged 3 years or older. Hepatitis C virus sustained virus response is as high as 97%. Therefore, if direct antiviral agents can be proven to be safe and well tolerated in very young children, HCV eradication could be planned after the first screening.
Collapse
Affiliation(s)
- Maria Grazia Clemente
- Pediatric Clinic, Clinical Epidemiology and Medical Statistics Unit, Hygiene and Preventive Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari (SS), Italy.
| | - Roberto Antonucci
- Pediatric Clinic, Clinical Epidemiology and Medical Statistics Unit, Hygiene and Preventive Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari (SS), Italy
| | - Giovanni Sotgiu
- Pediatric Clinic, Clinical Epidemiology and Medical Statistics Unit, Hygiene and Preventive Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari (SS), Italy
| | - Marco Dettori
- Pediatric Clinic, Clinical Epidemiology and Medical Statistics Unit, Hygiene and Preventive Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari (SS), Italy
| | - Andrea Piana
- Pediatric Clinic, Clinical Epidemiology and Medical Statistics Unit, Hygiene and Preventive Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari (SS), Italy
| | - Pietro Vajro
- Pediatrics - Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi (SA), Italy
| |
Collapse
|
|
9
|
Xing YF, Wei CS, Zhou TR, Huang DP, Zhong WC, Chen B, Jin H, Hu XY, Yang ZY, He Q, Jiang KP, Jiang JM, Hu ZB, Deng X, Yang F, Li FY, Zhao G, Wang LC, Mi YQ, Gong ZJ, Guo P, Wu JH, Shi WQ, Yang HZ, Zhou DQ, Tong GD. Efficacy of a Chinese herbal formula on hepatitis B e antigen-positive chronic hepatitis B patients. World J Gastroenterol 2020; 26:4501-4522. [PMID: 32874061 PMCID: PMC7438193 DOI: 10.3748/wjg.v26.i30.4501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/29/2020] [Accepted: 07/22/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND No guideline recommends antiviral therapy for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients with persistently normal alanine aminotransferase levels and a high hepatitis B virus (HBV) DNA viral load. AIM To evaluate the feasibility and safety of a Chinese herbal formula as a therapeutic option for chronic HBV infection. METHODS In total, 395 patients (30-65 years old) with confirmed HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase were randomized to receive either Chinese herbal formula or placebo for 96 wk. Endpoints to evaluate therapeutic efficacy included: (1) HBV DNA levels decreased to less than 4 log10 IU/mL at weeks 48 and 96; and (2) HBeAg clearance and seroconversion rates at weeks 48 and 96. RESULTS HBV DNA levels ≤ 4 log10 IU/mL were 10.05% at week 48 and 18.59% at week 96 in the treatment group. The HBeAg clearance and conversion rates were 8.54% and 8.04% at week 48 and 16.08% and 14.57% at week 96, respectively. However, HBV DNA levels ≤ 4 log10 IU/mL were 2.55% and 2.55% at weeks 48 and 96, respectively, and the HBeAg clearance rates were 3.06% and 5.61% at weeks 48 and 96, respectively, in the control group. The quantitative hepatitis B surface antigen and HBeAg levels at baseline and changes during the treatment period as well as the alanine aminotransferase elevation at weeks 12 and 24 were strong predictors of HBeAg clearance. CONCLUSION High rates of HBV DNA reduction, HBeAg clearance and seroconversion could be achieved with Chinese herbal formula treatments, and the treatments were relatively safe for HBeAg-positive chronic hepatitis B-infected patients with persistently normal alanine aminotransferase. The ability of the compound to modulate host immune function probably contributed to this effect.
Collapse
Affiliation(s)
- Yu-Feng Xing
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Chun-Shan Wei
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Tian-Ran Zhou
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Dan-Ping Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Wei-Chao Zhong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Bin Chen
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Hua Jin
- Department of Integrated Traditional and Western Medicine on Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xiao-Yu Hu
- Department of Infectious Disease, The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610032, Sichuan Province, China
| | - Zhi-Yun Yang
- Department of Integrated Traditional and Western Medicine on Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Qing He
- The First Department of Hepatology, Shenzhen No. 3 People’s Hospital, Shenzhen 518100, Guangdong Province, China
| | - Kai-Ping Jiang
- Department of Hepatology, Foshan Hospital of Traditional Chinese Medicine, Foshan 528000, Guangdong Province, China
| | - Jun-Min Jiang
- Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Zhen-Bin Hu
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530012, Guangxi Province, China
| | - Xin Deng
- Department of Hepatology, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning 530012, Guangxi Province, China
| | - Fan Yang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430060, Hubei Province, China
| | - Feng-Yi Li
- Treatment and Research Center of Infectious Disease, 302 Military Hospital of China, Beijing 100039, China
| | - Gang Zhao
- Department of Hepatology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201204, China
| | - Li-Chun Wang
- Center of Infectious Disease, Huaxi Hospital, Sichuan University, Chengdu 610044, Sichuan Province, China
| | - Yu-Qiang Mi
- Department of Infectious Disease, Tianjin Infectious Disease Hospital, Tianjin 300192, China
| | - Zuo-Jiong Gong
- Department of Infectious Disease, Hubei People’s Hospital, Wuhan 430060, Hubei Province, China
| | - Peng Guo
- Department of Hepatology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100080, China
| | - Jian-Hua Wu
- Center of Hepatology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361009, Fujian Province, China
| | - Wei-Qun Shi
- Department of Hepatology, Xinhua Hospital, Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang Province, China
| | - Hong-Zhi Yang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510620, Guangdong Province, China
| | - Da-Qiao Zhou
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Guang-Dong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| |
Collapse
|
|
10
|
Li J, Dong XQ, Wu Z, Ma AL, Xie SB, Zhang XQ, Zhang ZQ, Zhang DZ, Zhao WF, Zhang G, Cheng J, Xie Q, Li J, Zou ZQ, Liu YX, Wang GQ, Zhao H. Unsatisfying antiviral therapeutic effect in patients with mother-to-child transmissed chronic hepatitis B virus infection: a prospective multi-center clinical study. Chin Med J (Engl) 2020; 132:2647-2656. [PMID: 31725459 PMCID: PMC6940093 DOI: 10.1097/cm9.0000000000000522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group. Methods: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected. Results: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ2 = –2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response. Conclusion: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission. Trial Registration: NCT01962155; https://clinicaltrials.gov.
Collapse
Affiliation(s)
- Jun Li
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, Beijing 100034, China
| | - Xiao-Qin Dong
- Department of Infectious Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Zhao Wu
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, Beijing 100034, China
| | - An-Lin Ma
- Department of Infectious Diseases, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shi-Bin Xie
- Department of Infectious Diseases, The Third Affiliated Hospital Sun Yat-Sen University, Guangzhou, Guangdong 510000, China
| | - Xu-Qing Zhang
- Department of Infectious Diseases, South West Hospital Affiliated to Third Military Medical University, Chongqing 400038, China
| | - Zhan-Qing Zhang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, China
| | - Da-Zhi Zhang
- Department of Infectious Diseases, Second Affiliated Hospital of Chongqing Medical University, Chongqing 404000, China
| | - Wei-Feng Zhao
- Department of Infectious Diseases, Xinxiang Medical University Third Hospital, Xinxiang, Henan 453003, China
| | - Guo Zhang
- Department of Infectious Diseases, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, China
| | - Jun Cheng
- Department of Infectious Diseases, Di Tan Hospital Affiliated to Capital Medical University, Beijing 100015, China
| | - Qing Xie
- Department of Infectious Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200090, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Zhi-Qiang Zou
- Department of Infectious Diseases, Yantai City Hospital for Infectious Disease, Yantai, Shandong 264001, China
| | - Ying-Xia Liu
- Shenzhen Key Laboratory of Pathogen and Immunity, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong 518034, China
| | - Gui-Qiang Wang
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, Beijing 100034, China.,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310085, China.,Department of Infectious Diseases, Peking University International Hospital, Beijing 102206, China
| | - Hong Zhao
- Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, Beijing 100034, China.,Department of Infectious Diseases, Peking University International Hospital, Beijing 102206, China
| | | |
Collapse
|
|
11
|
Early treatment of chronic hepatitis B in children: Everything to play for? J Hepatol 2020; 72:802-803. [PMID: 32067804 DOI: 10.1016/j.jhep.2019.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 12/16/2022]
|
|
12
|
Gill US, Battisti A, Kennedy PTF. Emerging tools in the changing landscape of chronic hepatitis B management. Expert Rev Anti Infect Ther 2019; 17:943-955. [PMID: 31738607 DOI: 10.1080/14787210.2019.1694906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: The availability of a preventative vaccine, interferon, and nucleos(t)ide analogs have provided progress in the control of chronic hepatitis B (CHB). Despite this, it remains a major contributor to global morbidity and mortality. Developments in our understanding of the pathogenesis of CHB and the emergence of new therapies are paving the way, as we move toward HBV cure.Areas covered: We performed bibliographical searches of online databases to review the literature regarding conventional disease phases of CHB. We provide the latest evidence challenging the perception of the natural history of CHB, noting that previously considered quiescent disease phases may not represent benign disease states devoid of progression. We explore the use of potential novel immunological and viral tools which should enhance disease stratification and management decisions in the coming years. Finally, we discuss the timing of treatment and how this could be initiated earlier to improve treatment outcomes, preventing sequelae of chronic infection.Expert opinion: The treatment paradigm in CHB is set to change with multiple novel agents in early phase clinical trials with the aim of a functional cure. An improved understanding of disease pathogenesis and the timing of treatment will be critical to the success of new therapies.
Collapse
Affiliation(s)
- Upkar S Gill
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Arianna Battisti
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| |
Collapse
|
|
13
|
Ling SC, Mogul D. Treatment of infants with hepatitis B virus: A window of opportunity? J Hepatol 2019; 71:856-858. [PMID: 31506188 DOI: 10.1016/j.jhep.2019.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Simon C Ling
- The Hospital for Sick Children, Division of Gastroenterology, Hepatology and Nutrition, and Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
| | - Douglas Mogul
- Division of Pediatric Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
14
|
Bertoletti A, Le Bert N. Immunotherapy for Chronic Hepatitis B Virus Infection. Gut Liver 2019; 12:497-507. [PMID: 29316747 PMCID: PMC6143456 DOI: 10.5009/gnl17233] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 08/15/2017] [Accepted: 09/13/2017] [Indexed: 12/14/2022] Open
Abstract
While new therapies for chronic hepatitis C virus infection have delivered remarkable cure rates, curative therapies for chronic hepatitis B virus (HBV) infection remain a distant goal. Although current direct antiviral therapies are very efficient in controlling viral replication and limiting the progression to cirrhosis, these treatments require lifelong administration due to the frequent viral rebound upon treatment cessation, and immune modulation with interferon is only effective in a subgroup of patients. Specific immunotherapies can offer the possibility of eliminating or at least stably maintaining low levels of HBV replication under the control of a functional host antiviral response. Here, we review the development of immune cell therapy for HBV, highlighting the potential antiviral efficiency and potential toxicities in different groups of chronically infected HBV patients. We also discuss the chronic hepatitis B patient populations that best benefit from therapeutic immune interventions.
Collapse
Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore.,Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, A*STAR, Singapore
| | - Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore.,Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, A*STAR, Singapore
| |
Collapse
|
|
15
|
Chen L, Zhang Y, Zhang S, Chen Y, Shu X, Lai J, Cao H, Lian Y, Stamataki Z, Huang Y. A novel T-cell epitope in the transmembrane region of the hepatitis B virus envelope protein responds upon dendritic cell expansion. Arch Virol 2018; 164:483-495. [PMID: 30415392 PMCID: PMC6373280 DOI: 10.1007/s00705-018-4095-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 10/21/2018] [Indexed: 12/17/2022]
Abstract
Restoring antiviral immunity is a promising immunotherapeutic approach to the treatment of chronic hepatitis B virus (HBV) infection. Dendritic cells play a crucial role in triggering antiviral immunity. In this study, we identified immunodominant epitopes prevalent in CD8+ T cell responses. We characterized the hierarchy of HBV epitopes targeted by CD8+ T cells following autologous monocyte-derived dendritic cell (moDC) expansion in HBV-infected subjects with distinct disease stages: treatment-naïve (TN group, n = 168), treatment with complete virological response (TR group, n = 72), and resolved HBV infection (RS group, n = 28). T cell responses against 32 HBV epitopes were measured upon moDC expansion. Several subdominant epitopes that triggered HBV-specific CD8+ T cell responses were identified. These epitopes’ responses varied in individuals with different disease stages. Moreover, the most immunodominant and immunoprevalent epitope included the envelope residues 256-270 (Env256-270), corresponding to amino acid residues 93-107 in the small HBV surface protein (SHBs) across three patient groups. The frequency of Env256-270-specific interferon-γ-producing T cells was the highest in the RS group and the lowest in the TN group. In addition, individuals with HLA-A*02:03/02:06/02:07 were capable of responding to Env256-270. Env256-270-specific CD8+ T cells tolerated amino acid variations within the epitope detected in HBV genotypes B and C. This suggests that Env256-270 in SHBs is crucial in HBV-specific T cell immunity following autologous moDC expansion. It might be a potential target epitope for dendritic-cell-based immunotherapy for CHB patients with complete viral suppression by long-term NAs treatment.
Collapse
Affiliation(s)
- Lubiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Ying Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Shaoquan Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Youming Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Xin Shu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Jing Lai
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Hong Cao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zania Stamataki
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Yuehua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, China.
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
|
16
|
Immune Ecosystem of Virus-Infected Host Tissues. Int J Mol Sci 2018; 19:ijms19051379. [PMID: 29734779 PMCID: PMC5983771 DOI: 10.3390/ijms19051379] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 04/30/2018] [Accepted: 05/03/2018] [Indexed: 12/11/2022] Open
Abstract
Virus infected host cells serve as a central immune ecological niche during viral infection and replication and stimulate the host immune response via molecular signaling. The viral infection and multiplication process involves complex intracellular molecular interactions between viral components and the host factors. Various types of host cells are also involved to modulate immune factors in delicate and dynamic equilibrium to maintain a balanced immune ecosystem in an infected host tissue. Antiviral host arsenals are equipped to combat or eliminate viral invasion. However, viruses have evolved with strategies to counter against antiviral immunity or hijack cellular machinery to survive inside host tissue for their multiplication. However, host immune systems have also evolved to neutralize the infection; which, in turn, either clears the virus from the infected host or causes immune-mediated host tissue injury. A complex relationship between viral pathogenesis and host antiviral defense could define the immune ecosystem of virus-infected host tissues. Understanding of the molecular mechanism underlying this ecosystem would uncover strategies to modulate host immune function for antiviral therapeutics. This review presents past and present updates of immune-ecological components of virus infected host tissue and explains how viruses subvert the host immune surveillances.
Collapse
|
|
17
|
Maini MK, Pallett LJ. Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand. Lancet Gastroenterol Hepatol 2018; 3:192-202. [PMID: 29870733 DOI: 10.1016/s2468-1253(18)30007-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 09/18/2017] [Accepted: 09/22/2017] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) remains a major cause of morbidity and mortality worldwide. Treatments that can induce functional cure in patients chronically infected with this hepatotropic, non-cytopathic virus are desperately needed. Attempts to use therapeutic vaccines to expand the weak antiviral T-cell response and induce sustained immunity have been unsuccessful. However, exciting progress has been made in defining the molecular defects that must be overcome to harness T-cell immunity. A large arsenal of immunotherapeutic agents and direct-acting antivirals targeting multiple steps of the viral lifecycle is emerging. In this Review, we discuss how to translate the new insights into T-cell manipulation, combined with better understanding of patient heterogeneity, into optimisation of therapeutic vaccines against HBV. We review the opportunities and risks involved in boosting endogenous T-cell responses using combinations of next generation therapeutic vaccines and immunotherapy agents.
Collapse
Affiliation(s)
- Mala K Maini
- Division of Infection and Immunity and Institute of Immunity and Transplantation, University College London, London, UK.
| | - Laura J Pallett
- Division of Infection and Immunity and Institute of Immunity and Transplantation, University College London, London, UK
| |
Collapse
|
|
18
|
Vyas AK, Jindal A, Hissar S, Ramakrishna G, Trehanpati N. Immune balance in Hepatitis B Infection: Present and Future Therapies. Scand J Immunol 2017; 86:4-14. [PMID: 28387980 DOI: 10.1111/sji.12553] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 03/28/2017] [Indexed: 12/16/2022]
Abstract
Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about half a million people die every year. India represents the second largest pool of chronic HBV infections with an estimated 40 million chronically infected patients. Persistence or clearance of HBV infection mainly depends upon host immune responses. Chronically infected individuals remain in immune tolerant phase unless HBV flares and leads to the development of chronic active hepatitis or acute-on-chronic liver failure. Strategies based on inhibition of viral replication (nucleoside analogues) or immune modulation (interferons) as monotherapy, or in combination in sequential therapies, are currently being used globally for reducing HBV viral load and mediating HBsAg clearance. However, the immune status and current therapies for promoting sustained virological responses in HBV-infected patients remain suboptimal. Elimination of cccDNA is major challenge for future therapies, and new molecules such as NTCP, Toll-like receptor (TLR)7 agonist (GS9620) and cyclophilin have emerged as potential targets for preventing HBV entry and replication. Other than these, HBV cccDNA elimination is the major target for future therapies.
Collapse
Affiliation(s)
- A K Vyas
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| | - A Jindal
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - S Hissar
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| | - G Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| | - N Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| |
Collapse
|
|
19
|
Tolerance and immunity to pathogens in early life: insights from HBV infection. Semin Immunopathol 2017; 39:643-652. [PMID: 28685270 PMCID: PMC5711997 DOI: 10.1007/s00281-017-0641-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023]
Abstract
Immunity is not static but varies with age. The immune system of a newborn infant is not "defective" or "immature." Rather, there are distinct features of innate and adaptive immunity from fetal life to adulthood, which may alter the susceptibility of newborn infants to infections compared to adults. Increased protection to certain infectious diseases during early life may benefit from a dampened immune response as a result of decreased immune pathology. This concept may offer an alternative interpretation of the different pathological manifestations clinically observed in hepatitis B virus (HBV)-infected patients during the natural history of infection. Herein, we review the immune pathological features of HBV infection from early life to adulthood and challenge the concept of a generic immune tolerant state in young people. We then discuss how the different clinical and virological manifestations during HBV infection may be related to the differential antiviral immunity and pro-inflammatory capacity generated at different ages. Lastly, we address the potential to consider earlier therapeutic intervention in HBV-infected young patients to achieve effective immune control leading to better outcomes.
Collapse
|
|
20
|
Zhou C, Li C, Gong GZ, Wang S, Zhang JM, Xu DZ, Guo LM, Ren H, Xu M, Xie Q, Pan C, Xu J, Hu Z, Geng S, Zhou X, Wang X, Zhou X, Mi H, Zhao G, Yu W, Wen YM, Huang L, Wang XY, Wang B. Analysis of immunological mechanisms exerted by HBsAg-HBIG therapeutic vaccine combined with Adefovir in chronic hepatitis B patients. Hum Vaccin Immunother 2017; 13:1989-1996. [PMID: 28665747 DOI: 10.1080/21645515.2017.1335840] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-β and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-β and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.
Collapse
Affiliation(s)
- Chenliang Zhou
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Chaofan Li
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Guo-Zhong Gong
- b The Second Xiangya Hospital , Central South University , Changsha , People's Republic of China
| | - Shuang Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Ji-Ming Zhang
- c Huashan Hospital , Fudan University , Shanghai , People's Republic of China
| | - Dao-Zhen Xu
- d Beijing Ditan Hospital , Capital Medical University , Beijing , People's Republic of China
| | - Li-Min Guo
- d Beijing Ditan Hospital , Capital Medical University , Beijing , People's Republic of China
| | - Hong Ren
- e The Second Affiliated Hospital , Chongqing Medical University , Chongqing , People's Republic of China
| | - Min Xu
- f Guangzhou Eighth People's Hospital , Guangzhou , People's Republic of China
| | - Qing Xie
- g Ruijin Hospital , Jiaotong University , Shanghai , People's Republic of China
| | - Chen Pan
- h Fuzhou Infectious Disease Hospital , Fuzhou , People's Republic of China
| | - Jie Xu
- i The Third People's Hospital , Jiaotong University , Shanghai , People's Republic of China
| | - Zhongyu Hu
- j National Institutes for Food and Drug Control , Beijing , People's Republic of China
| | - Shuang Geng
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Xian Zhou
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Xianzheng Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Xiaoyu Zhou
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Haili Mi
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Gan Zhao
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Wencong Yu
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Yu-Mei Wen
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Lihua Huang
- k Wuxi Fifth People's Hospital , Wuxi , People's Republic of China
| | - Xuan-Yi Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| | - Bin Wang
- a Key Laboratory of Medical Molecular Virology , MoE/MoH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University , Shanghai , People's Republic of China
| |
Collapse
|
|
21
|
Poortahmasebi V, Salarian A, Amiri M, Poorebrahim M, Jazayeri SM, Ataei A, Asghari M, Alavian SM. Integrated Analysis of Gene Expression Profiles Reveals Deregulation of the Immune Response Genes during Different Phases of Chronic Hepatitis B Infection. HEPATITIS MONTHLY 2017; 17. [DOI: 10.5812/hepatmon.42237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
22
|
Ayoub WS, Cohen E. Hepatitis B Management in the Pregnant Patient: An Update. J Clin Transl Hepatol 2016; 4:241-247. [PMID: 27777892 PMCID: PMC5075007 DOI: 10.14218/jcth.2016.00014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/17/2016] [Accepted: 09/04/2016] [Indexed: 12/23/2022] Open
Abstract
Chronic hepatitis B is a worldwide disease, with significant burden on health care systems. While universal vaccination programs have led to an overall decrease in incidence of transmission of hepatitis B, unfortunately, there remain large areas in the world where vaccination against hepatitis B is not practiced. In addition, vertical transmission of hepatitis B persists as a major concern. Hepatitis B treatment of the pregnant patient requires a thorough assessment of disease activity and close monitoring for flares, regardless of initiation of antiviral therapy. We discuss, in this article, the current and emergent strategies which aim to reduce the rate of transmission of hepatitis B from the pregnant mother to the infant and we review the updated guidelines regarding management of liver disease in pregnant women with hepatitis B.
Collapse
Affiliation(s)
- Walid S. Ayoub
- Department of Gastroenterology and Hepatology, Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA, USA
- Department of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Erica Cohen
- Department of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA, USA
| |
Collapse
|
|
23
|
Abstract
Chronic hepatitis B infection in the female population has implications not just for the individual but for her children as well. This article discusses the natural history of hepatitis B and how it plays an important role in hepatitis B virus (HBV) transmission, the current strategies and new strategies to control HBV and reduce transmission, and the updated guidelines for the management of HBV.
Collapse
Affiliation(s)
- Erica Cohen
- Division of Gastroenterology, Cedars Sinai Medical Center, 8730 Alden Dr, Los Angeles, CA 90025, USA
| | - Tram T Tran
- Liver Transplant, Cedars Sinai Medical Center, 8900 Beverly Boulevard, Los Angeles, CA 90048, USA.
| |
Collapse
|
|
24
|
Hadžić N, Bansal S. Hepatitis B virus in children: More therapeutic options-but unknown and known unknowns still present. Hepatology 2016; 63:360-2. [PMID: 26361247 DOI: 10.1002/hep.28154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 09/10/2015] [Indexed: 01/12/2023]
Affiliation(s)
- Nedim Hadžić
- Pediatric Center for Hepatology, Gastroenterology and Nutrition King's College Hospital, London, Denmark Hill, United KIngdom
| | - Sanjay Bansal
- Pediatric Center for Hepatology, Gastroenterology and Nutrition King's College Hospital, London, Denmark Hill, United KIngdom
| |
Collapse
|
|
25
|
Zhang QF, Shao JY, Yin WW, Xia Y, Chen L, Wang X, Hu HD, Hu P, Ren H, Zhang DZ. Altered Immune Profiles of Natural Killer Cells in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0160171. [PMID: 27513564 PMCID: PMC4981347 DOI: 10.1371/journal.pone.0160171] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 07/14/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells are the main effective component of the innate immune system that responds to chronic hepatitis B (CHB) infection. Although numerous studies have reported the immune profiles of NK cells in CHB patients, they are limited by inconsistent results. Thus, we performed a meta-analysis to characterize reliably the immune profiles of NK cells after CHB infection, specifically frequency, phenotype, and function. METHODS A literature search of the computer databases MEDLINE, PUBMED, EMBASE, and Cochrane Center Register of Controlled Trails was performed and 19 studies were selected. The standard mean difference (SMD) and 95% confidence interval (CI) of each continuous variable was estimated with a fixed effects model when I2 < 50% for the test for heterogeneity, or the random effects model otherwise. Publication bias was evaluated using Begg's and Egger's tests. RESULTS The meta-analysis of publications that reported frequency of peripheral NK cells showed that NK cell levels in CHB patients were significantly lower compared with that of healthy controls. A higher frequency of CD56bright NK subsets was found in CHB patients, but the CD56dim NK subsets of CHB patients and healthy controls were similar. CHB patients before and after antiviral therapy with nucleotide analogues (NUCs) showed no statistical difference in NK frequency. The activating receptors were upregulated, whereas inhibitory receptors were comparable in the peripheral NK cells of CHB individuals and healthy controls. NK cells of CHB patients displayed higher cytotoxic potency as evidenced by CD107a protein levels and conserved potency to produce interferon-gamma (IFNγ), compared with their healthy counterparts. CONCLUSION Our results revealed that CHB patients had a lower frequency of NK cells compared with healthy individuals not treatable with antiviral NUC therapy. With an activating phenotype, NK cells in CHB patients showed better cytotoxic potency and conserved IFNγ production.
Collapse
Affiliation(s)
- Qiong-Fang Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Jian-Ying Shao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Wen-Wei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Yang Xia
- Department of Urinary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqiong, China
| | - Ling Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Xing Wang
- Department of Orthopedic Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqiong, China
| | - Huai-Dong Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Da-Zhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
- * E-mail:
| |
Collapse
|
|
26
|
Wang X, Dong A, Xiao J, Zhou X, Mi H, Xu H, Zhang J, Wang B. Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice. Cell Mol Immunol 2015; 13:850-861. [PMID: 26166767 DOI: 10.1038/cmi.2015.64] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 06/06/2015] [Accepted: 06/06/2015] [Indexed: 12/14/2022] Open
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells (DCs) could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus (HBV) therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine (rHBVvac) in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic (HBsAg-Tg) animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-γ production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8+ T cells from immunized animals, antigen-specific CD8+ T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients.
Collapse
Affiliation(s)
- Xianzheng Wang
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China
| | - Aihua Dong
- NCPC New Drug R&D Co., Ltd., Shijiazhuang, China
| | - Jingjing Xiao
- Medical Center of Diagnostics and Treatment for Cervical Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Xingjun Zhou
- NCPC New Drug R&D Co., Ltd., Shijiazhuang, China
| | - Haili Mi
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hanqian Xu
- State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, China
| | - Jiming Zhang
- Department of Infectious Disease, Huashang Hospital, Fudan University, Shanghai, China
| | - Bin Wang
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, Shanghai Medical College, Fudan University, Shanghai, China.,State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing, China
| |
Collapse
|
|
27
|
Heiberg IL, Pallett LJ, Winther TN, Høgh B, Maini MK, Peppa D. Defective natural killer cell anti-viral capacity in paediatric HBV infection. Clin Exp Immunol 2015; 179:466-76. [PMID: 25311087 PMCID: PMC4337679 DOI: 10.1111/cei.12470] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2014] [Indexed: 12/11/2022] Open
Abstract
Natural killer (NK) cells exhibit dysregulated effector function in adult chronic hepatitis B virus (HBV) infection (CHB), which may contribute to virus persistence. The role of NK cells in children infected perinatally with HBV is less studied. Access to a unique cohort enabled the cross-sectional evaluation of NK cell frequency, phenotype and function in HBV-infected children relative to uninfected children. We observed a selective defect in NK cell interferon (IFN)-γ production, with conserved cytolytic function, mirroring the functional dichotomy observed in adult infection. Reduced expression of NKp30 on NK cells suggests a role of impaired NK-dendritic cell (DC) cellular interactions as a potential mechanism leading to reduced IFN-γ production. The finding that NK cells are already defective in paediatric CHB, albeit less extensively than in adult CHB, has potential implications for the timing of anti-viral therapy aiming to restore immune control.
Collapse
Affiliation(s)
- I L Heiberg
- Department of Paediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | | | | |
Collapse
|
|
28
|
Carey I, Bruce M, Horner M, Zen Y, D'Antiga L, Bansal S, Vergani D, Mieli-Vergani G. HBsAg plasma level kinetics: a new role for an old marker as a therapy response predictor in vertically infected children on combination therapy. J Viral Hepat 2015; 22:441-52. [PMID: 25278170 DOI: 10.1111/jvh.12316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
We aimed to investigate the ability of HBsAg plasma level kinetics to predict therapy response by studying 23 children with infancy-acquired chronic hepatitis B (CHB) during combination sequential therapy with lead-in lamivudine (LAM) and add-on interferon-α (IFN-α) [5 responders (R = anti-HBs seroconversion) and 18 nonresponders (NR)] and to assess their relationship with pretreatment intrahepatic HBV-DNA and cccDNA and HBsAg and HBcAg liver expression. Plasma HBsAg levels were measured in samples before (treatment week 0 = TW0), during (TW9, TW28, TW52) and after (follow-up week = FUW24) therapy by Abbott ARCHITECT(®) assay [log10 IU/mL]. Baseline liver HBV-DNA and cccDNA were quantified by real-time TaqMan PCR [log10 copies/ng genomic DNA]. HBsAg and HBcAg liver expression was evaluated by immunostaining of formalin-fixed, paraffin-embedded specimens [number of positive cells/1000 hepatocytes]. All results are presented as medians. Plasma: at baseline, on-treatment and during follow-up, HBsAg levels were lower in R than NR (TW0: 4.36 vs 4.75;TW28: 2.44 vs 4.35;TW52: 0 vs 4.08 and FUW24: 0.17 vs 4.35, all P < 0.05). Liver: baseline HBV-DNA (3.82 vs 4.71, P = 0.16) and cccDNA (1.98 vs 2.26, P = 0.18) tended to be lower in R than NR, HBsAg expression was lower in R than NR (0.5 vs 4.7, P = 0.03), and HBcAg expression was similar between R and NR. There were positive correlations between plasma HBsAg levels and liver HBV-DNA (r = 0.44, P = 0.04), cccDNA (r = 0.41, P = 0.04) and HBsAg liver expression (r = 0.38, P = 0.05). Lower baseline HBsAg plasma levels, lower HBsAg expression in liver and on-treatment decline of plasma HBsAg levels heralds HBsAg clearance and response to treatment in tolerant children with CHB.
Collapse
Affiliation(s)
- I Carey
- Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London, UK
| | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology 2015; 61:712-21. [PMID: 25048716 PMCID: PMC4575407 DOI: 10.1002/hep.27323] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 07/12/2014] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens.
Collapse
Affiliation(s)
- Barbara Rehermann
- Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health, DHHSBethesda, MD, USA
| | - Antonio Bertoletti
- Emerging Infectious Diseases, Duke-NUS Graduate Medical School
- Singapore Institute for Clinical Sciences, A* STARSingapore
| |
Collapse
|
|
30
|
Luo G, Feng X, Huang Y, Yi T, Wang D, Guo X, Yan H, Zhang G. Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B. Mol Med Rep 2014; 11:1284-91. [PMID: 25371014 DOI: 10.3892/mmr.2014.2836] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 07/25/2014] [Indexed: 11/05/2022] Open
Abstract
A weak T‑cell immune response to the hepatitis B virus (HBV) is hypothesized to be the primary cause of chronic HBV infection. Emerging evidence suggests that long‑term effective antiviral therapy restores the HBV‑specific T‑cell response from exhaustion. However, the extent to which the cellular immune response can be restored following the persistent suppression of HBV replication by antiviral therapy remains unclear. In order to investigate this question, 46 patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues who demonstrated persistent suppression of HBV replication [defined as undetectable HBV DNA, hepatitis B e antigen (HBeAg) negative and adherence to antiviral therapy], 22 untreated CHB patients, 15 patients with acute hepatitis B (AHB) and 10 healthy adults were recruited. HBV‑specific interferon‑γ enzyme‑linked immunospot (IFN‑γ ELISPOT) assay and HBV‑specific T‑cell proliferation analysis were performed with a panel of overlapping peptides covering the envelope and core antigens. Data from this study showed that the HBV‑specific immune responses to the peptide pools of the envelope and core protein in the treated patients were stronger than those in the untreated CHB patients, but significantly weaker than those in the AHB patients and healthy adults. A higher frequency of response to S than C peptide pools was confirmed by the IFN‑γ ELISPOT assay in the treated CHB patients. The restoration of antiviral immunity was clearly associated with a reduction in HBV DNA and the duration of HBV DNA suppression. In conclusion, the HBV‑specific immune responses in the CHB patients can be significantly restored from exhaustion following the persistent suppression of HBV replication as a result of antiviral treatment with nucleos(t)ide analogues.
Collapse
Affiliation(s)
- Guangcheng Luo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xia Feng
- Research Center for Infection and Immunity, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Yanxiang Huang
- Research Center for Infection and Immunity, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Tingting Yi
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Dongsheng Wang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Huiping Yan
- Research Center for Infection and Immunity, Beijing You'an Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Guoyuan Zhang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| |
Collapse
|
|
31
|
Bertoletti A, Hong M. Age-Dependent Immune Events during HBV Infection from Birth to Adulthood: An Alternative Interpretation. Front Immunol 2014; 5:441. [PMID: 25295036 PMCID: PMC4172010 DOI: 10.3389/fimmu.2014.00441] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 08/31/2014] [Indexed: 12/17/2022] Open
Abstract
Immune responses change during the life of an individual. While this concept has been well accepted for adaptive immunity, only recently it is becoming clear that the innate immune responses also acquire distinct features in different phases of life. We believe that this concept can offer a different interpretation of the pathological manifestations that can be observed in HBV-infected subjects during the patient’s life. Here, we will review the age-related immunopathological features of HBV infection and discuss how the different virological and clinical manifestations might be linked to the developmental pathway of the immune system from newborns to adults. We will discuss how the age of patients can affect the degree of inflammatory responses, but not the levels of antiviral specific immunity. We then propose that the different clinical manifestations occurring during the natural history of HBV infection are related to the host ability to trigger an inflammatory immune response.
Collapse
Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases (EID) Program, Duke-NUS Graduate Medical School , Singapore ; Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (ASTAR) , Singapore
| | - Michelle Hong
- Emerging Infectious Diseases (EID) Program, Duke-NUS Graduate Medical School , Singapore ; Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (ASTAR) , Singapore
| |
Collapse
|
|
32
|
Bertoletti A, Kennedy PT. The immune tolerant phase of chronic HBV infection: new perspectives on an old concept. Cell Mol Immunol 2014; 12:258-63. [PMID: 25176526 DOI: 10.1038/cmi.2014.79] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 07/28/2014] [Accepted: 07/29/2014] [Indexed: 12/23/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant (IT) phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of "tolerance' has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.
Collapse
Affiliation(s)
- Antonio Bertoletti
- 1] Emerging Infectious Diseases (EID) Program, Duke-NUS Graduate Medical School, Singapore [2] Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR), Singapore
| | - Patrick T Kennedy
- Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
| |
Collapse
|
|
33
|
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.
Collapse
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
| | | |
Collapse
|
|
34
|
Mekky MA. To treat or not to treat the "immunotolerant phase" of hepatitis B infection: A tunnel of controversy. World J Hepatol 2014; 6:226-229. [PMID: 24799991 PMCID: PMC4009478 DOI: 10.4254/wjh.v6.i4.226] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Revised: 12/08/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem, with an estimated 350 million people worldwide chronically infected and approximately 500000 who die annually from HBV-related liver diseases. Management of chronic HBV is challenging and waves of guidelines emerge every year. One of the hottest topics and a matter of debate is the management of patients in their early immunotolerant phase of infection. With the lack of evidence, dealing with this particular subset of patients creates a great conflict with opposing views. In this review, the author highlights the pros and cons of these views and proposes a reasonable solution to resolve this dilemma.
Collapse
|
|
35
|
Xie X, Geng S, Liu H, Li C, Yang Y, Wang B. Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8(+) T cell. Hum Vaccin Immunother 2014; 10:1688-99. [PMID: 24643207 DOI: 10.4161/hv.28517] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Previously, we have reported that either CIM or PZQ, 2 clinical drugs, could be used to develop as adjuvants on HBV DNA vaccine to elicit both humoral and cellular immune responses. Here, we demonstrate that combinations of CIM and PZQ as adjuvants for a HBV DNA vaccine, could induce much stronger antigen specific CD4(+) and CD8(+) T cell responses compared either with CIM or PZQ alone. The synergistic effects of CIM plus PZQ to HBV DNA vaccine were observed on a higher IgG2a/IgG1 ratio, an increase of HBsAg-specific CD4(+) T cells capable of producing IFN-γ or IL-17A and a robust IFN-γ-, IL-17A-, or TNF-α-producing CD8(+) T cells to HBsAg. Most importantly, the antigen-specific CTL response was also elevated significantly, which is critical for the eradication of hepatitis B virus (HBV) infected cells. Using an HBsAg transgenic mouse model, the expression of HBsAg in the hepatic cells was also significantly reduced after immunized with pCD-S 2 in the presence of 0.5% CIM and 0.25% PZQ. Further investigations demonstrated that the synergistic effects of combination of CIM and PZQ were dependent on enhanced cytotoxic CD8(+) T cells, which was correlated with impaired activities of regulatory T cells. Therefore, combinations of CIM and PZQ have great potential to be used as effective adjuvants on DNA-based vaccinations for the treatment of chronic hepatitis B.
Collapse
Affiliation(s)
- Xiaoping Xie
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, PR China
| | - Shuang Geng
- Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, PR China
| | - Hu Liu
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, PR China
| | - Chaofan Li
- Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, PR China
| | - Yuqin Yang
- Shanghai Public Health Clinical Center affiliated to Fudan University; Shanghai, PR China
| | - Bin Wang
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, PR China; Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, PR China
| |
Collapse
|
|
36
|
Winther TN, Heiberg IL, Bang-Berthelsen CH, Pociot F, Hogh B. Hepatitis B surface antigen quantity positively correlates with plasma levels of microRNAs differentially expressed in immunological phases of chronic hepatitis B in children. PLoS One 2013; 8:e80384. [PMID: 24244683 PMCID: PMC3823657 DOI: 10.1371/journal.pone.0080384] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 10/11/2013] [Indexed: 01/05/2023] Open
Abstract
Background and Aim Children with chronic hepatitis B (CHB) are at high risk of progressive liver disease. It is suggested that a newly-identified panel of 16 microRNAs is important in the pathogenesis of CHB in children. Subviral hepatitis B surface antigen (HBsAg) particles are produced in large excess over infectious virions. Interestingly, circulating HBsAg particles have been shown to carry microRNAs. A thorough characterisation of the identified microRNAs and HBsAg over time in plasma from children with CHB may provide useful information about the natural course of childhood CHB. Patients and Methods A cohort of 42 children with CHB was followed over time. Three to five blood samples were obtained from each child at minimum intervals of half a year; in total 180 blood samples. Plasma levels of the 16 microRNAs previously identified were analysed by quantitative real-time polymerase-chain-reaction. Plasma HBsAg was quantified using ARCHITECT® HBsAg assay. Results The presence of 14/16 plasma microRNAs in children with CHB was confirmed. All 14 microRNAs were significantly differentially expressed in different immunological phases of the disease. MicroRNA plasma levels were highest in immune-tolerant children, lower in immune-active children, and reached the lowest values in immune-inactive children, p<0.001. Plasma levels of four microRNAs decreased significantly over time in immune-tolerant and immune-active children whereas the microRNA plasma levels were stable in immune-inactive children, p<0.004. HBsAg quantity was positively correlated with plasma levels of 11/14 microRNAs, p<0.004. Conclusion This is the first study to characterise plasma microRNAs and HBsAg over time in children with CHB. Our data suggest that plasma levels of selected microRNAs and HBsAg are inversely correlated with immunological control of CHB in children. Further studies are, however, needed to advance the understanding of microRNAs and HBsAg in the pathogenesis of CHB in children.
Collapse
Affiliation(s)
- Thilde Nordmann Winther
- Department of Paediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
- Diagnostic Unit and Center for Non-Coding RNA in Technology and Health, Glostrup Research Institute, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark
- * E-mail:
| | - Ida Louise Heiberg
- Department of Paediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Claus Heiner Bang-Berthelsen
- Diagnostic Unit and Center for Non-Coding RNA in Technology and Health, Glostrup Research Institute, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark
| | - Flemming Pociot
- Diagnostic Unit and Center for Non-Coding RNA in Technology and Health, Glostrup Research Institute, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark
| | - Birthe Hogh
- Department of Paediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
37
|
The L60V variation in hepatitis B virus core protein elicits new epitope-specific cytotoxic T lymphocytes and enhances viral replication. J Virol 2013; 87:8075-84. [PMID: 23678186 DOI: 10.1128/jvi.00577-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mutations in the core protein (HBc) of hepatitis B virus (HBV) are associated with aggressive hepatitis and advanced liver diseases in chronic hepatitis B (CHB). In this study, we identified the L60V variation in HBc that generates a new HLA-A2-restricted CD8(+) T cell epitope by screening an overlapping 9-mer peptide pool covering HBc and its variants. The nonameric epitope V60 was determined by structural and immunogenic analysis. The HBc L60V variation is correlated with hepatic necroinflammation and higher viral levels, and it may be associated with a poor prognosis in CHB patients. Immunization with the defined HBV epitope V60 peptide elicited specific cytotoxic T lymphocyte (CTL)-induced liver injury in HLA-A2(+) HBV transgenic mice. In addition, in vitro and in vivo experiments both demonstrated that the HBc L60V variation facilitates viral capsid assembly and increases HBV replication. These data suggest that the HBc L60V variation can impact both HBV replication and HBV-specific T cell responses. Therefore, our work provides further dissection of the impact of the HBc L60V variation, which orchestrates HBV replication, viral persistence, and immunopathogenesis during chronic viral infection.
Collapse
|
|
38
|
Poddar U, Yachha SK, Agarwal J, Krishnani N. Cure for immune-tolerant hepatitis B in children: is it an achievable target with sequential combo therapy with lamivudine and interferon? J Viral Hepat 2013; 20:311-6. [PMID: 23565612 DOI: 10.1111/jvh.12007] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 07/01/2012] [Indexed: 12/13/2022]
Abstract
We prospectively studied the HBsAg seroconversion with sequential combination therapy of lamivudine (LAM) and interferon (IFN) in hitherto untreatable 'immune-tolerant' chronic hepatitis B in children. In this case-control study, 28 children with immune-tolerant hepatitis B [HBsAg positive for >6 months with near normal aminotransferase level, minimal/no inflammation in liver histology and high viral load (HBV DNA>10(7) copies/mL)] were treated with LAM alone at 3 mg/kg/day for 8 weeks followed by LAM plus IFN alpha (5 MU/m(2) three times a week) for another 44 weeks. They were compared with 34 untreated children. HBV markers (HBsAg, HBeAg, anti-HBe, quantitative HBV DNA) were carried out at baseline, at the end of therapy and 6 monthly thereafter. The mean age was 5.9 ± 3.2 years and 24 were boys. End therapy response: HBe seroconversion was achieved in 11, and of these, five had complete response (HBsAg clearance), 11 did not respond and six had virologic response (DNA undetectable but no HBe seroconversion). Six months after therapy, 10 of the 11 (91%) originally seroconverted children remained seroconverted while one seroreverted. Six of the 28 (21.4%) children lost HBsAg and they remained HBsAg negative and anti-HBs positive on follow-up. After a mean follow-up of 21.1 ± 11.9 months, the status remained same in the responders but one of the nonresponders HBe seroconverted (39.3%). There were no serious side effects of therapy. It is possible to achieve a cure in more than one-fifth of immune-tolerant children with hepatitis B with the sequential combination of LAM and IFN.
Collapse
Affiliation(s)
- U Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India.
| | | | | | | |
Collapse
|
|
39
|
Hepatitis B surface antigen could contribute to the immunopathogenesis of hepatitis B virus infection. ISRN GASTROENTEROLOGY 2013; 2013:935295. [PMID: 23401786 PMCID: PMC3562682 DOI: 10.1155/2013/935295] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2012] [Accepted: 12/24/2012] [Indexed: 12/20/2022]
Abstract
Various findings concerning the clinical significance of quantitative changes in hepatitis B surface antigen (HBsAg) during the acute and chronic phase of hepatitis B virus (HBV) infection have been reported. In addition to being a biomarker of HBV-replication activity, it has been reported that HBsAg could contribute to the immunopathogenesis of HBV persistent infection. Moreover, HBsAg could become an attractive target for immune therapy, since the cellular and humeral immune response against HBsAg might be able to control the HBV replication and life cycle. However, several reports have described the immune suppressive function of HBsAg. HBsAg might suppress monocytes, dendritic cells (DCs), natural killer (NK), and natural killer T (NK-T) cells by direct interaction. On the other hand, cytotoxic T lymphocytes (CTLs) and helper T (Th) cells were exhausted by high amounts of HBsAg. In this paper, we focused on the immunological aspects of HBsAg, since better understanding of the interaction between HBsAg and immune cells could contribute to the development of an immune therapy as well as a biomarker of the state of HBV persistent infection.
Collapse
|
|
40
|
Boni C, Laccabue D, Lampertico P, Giuberti T, Viganò M, Schivazappa S, Alfieri A, Pesci M, Gaeta GB, Brancaccio G, Colombo M, Missale G, Ferrari C. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143:963-73.e9. [PMID: 22796241 DOI: 10.1053/j.gastro.2012.07.014] [Citation(s) in RCA: 296] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 06/29/2012] [Accepted: 07/03/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control. METHODS We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections. RESULTS Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. CONCLUSIONS In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.
Collapse
Affiliation(s)
- Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, Foster GR, Bertoletti A. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology 2012; 143:637-645. [PMID: 22710188 DOI: 10.1053/j.gastro.2012.06.009] [Citation(s) in RCA: 238] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Revised: 05/07/2012] [Accepted: 06/08/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance. METHODS We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells. RESULTS Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB. CONCLUSIONS HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.
Collapse
Affiliation(s)
- Patrick T F Kennedy
- Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England
| | - Elena Sandalova
- Infection & Immunity Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore
| | - Juandy Jo
- Infection & Immunity Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore
| | - Upkar Gill
- Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England
| | - Ines Ushiro-Lumb
- Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England
| | - Anthony T Tan
- Infection & Immunity Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore
| | - Sandhia Naik
- Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England
| | - Graham R Foster
- Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England
| | - Antonio Bertoletti
- Infection & Immunity Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore; Program Emerging Viral Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| |
Collapse
|
|
42
|
Penna A, Laccabue D, Libri I, Giuberti T, Schivazappa S, Alfieri A, Mori C, Canetti D, Lampertico P, Viganò M, Colombo M, Loggi E, Missale G, Ferrari C. Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis. J Hepatol 2012; 56:1239-46. [PMID: 22326467 DOI: 10.1016/j.jhep.2011.12.032] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 12/02/2011] [Accepted: 12/22/2011] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. METHODS HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. RESULTS Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. CONCLUSIONS IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.
Collapse
Affiliation(s)
- Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Liu Q, Zheng Y, Yu Y, Tan Q, Huang X. Identification of HLA-A*0201-restricted CD8+ T-cell epitope C₆₄₋₇₂ from hepatitis B virus core protein. Int Immunopharmacol 2012; 13:141-7. [PMID: 22480777 DOI: 10.1016/j.intimp.2012.03.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 03/20/2012] [Accepted: 03/20/2012] [Indexed: 12/22/2022]
Abstract
The efficacy of a potential therapeutic vaccine against chronic hepatitis B virus (HBV) infection depends on the development of strong and multi-specific T cell responses. The potency of CD8+ cytotoxic T lymphocyte (CTL) responses toward HBV core antigen (HBcAg) has been shown to be critical for the outcomes of HBV chronic infection. In this study we have identified a previously undescribed HLA-A*0201-restricted HBcAg-specific CTL epitope (HBcAg₆₄₋₇₂, C₆₄₋₇₂, ELMTLATWV). T2 binding assay showed that C₆₄₋₇₂ had high affinity to HLA-A*0201 molecule. Functionally, the peptide C₆₄₋₇₂ could induce peptide-specific CTLs both in vivo (HLA-A2.1/K(b) transgenic mice) and in vitro (PBLs of healthy HLA-A2.1+ donors), as demonstrated by interferon-γ (IFN-γ) secretion upon stimulation with C₆₄₋₇₂-pulsed T2 cells or autologous human dendritic cells (DCs) respectively. HLA-A*0201-C₆₄₋₇₂ tetramer staining revealed the presence of a significant population of C₆₄₋₇₂-specific CTLs in C₆₄₋₇₂-stimulated CD8+ T cells. Furthermore, the peptide-specific cytotoxic reactivity and the production of perforin and granzyme B of CTLs also increased after stimulation with C₆₄₋₇₂-pulsed autologous DCs. These results indicate that the newly identified epitope C₆₄₋₇₂ has potential to be used in the development of immunotherapeutic approaches to HBV infection.
Collapse
Affiliation(s)
- Qiuyan Liu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
| | | | | | | | | |
Collapse
|
|
44
|
Tran TT. Immune tolerant hepatitis B: a clinical dilemma. Gastroenterol Hepatol (N Y) 2011; 7:511-6. [PMID: 22298987 PMCID: PMC3264935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Chronic hepatitis B virus infection remains a global health concern, with perinatal transmission still a problem in many countries. Several new therapies for chronic hepatitis B virus infection have recently been introduced that can safely and effectively suppress viral replication with a low risk of resistance; thus, it has become increasingly tempting for many clinicians to treat patients in the immune tolerant stage of infection who have high levels of viremia yet persistently normal levels of transaminases. However, understanding the natural history of hepatitis B virus infection and how it pertains to disease progression, as well as how current therapies alter or do not alter this natural history, is important when deciding whether to treat these patients. This article will review the definition and natural history of immune tolerance, the current world guidelines and recommendations for treatment of immune tolerant patients, and data on the effectiveness of current therapies in this patient population.
Collapse
|