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He Q, Mao C, Chen Z, Duan F, Huang L, Hu R, Deng Y, Cheng J, Yang S, Zeng Y. Dynamic Changes of Growth and Thyroid Function in Young Children With Chronic Hepatitis B Treated With Peginterferon Monotherapy. Pediatr Infect Dis J 2025; 44:112-117. [PMID: 39348504 PMCID: PMC11731032 DOI: 10.1097/inf.0000000000004567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND Peginterferon (PegIFN) has shown promising results in the treatment of chronic hepatitis B (CHB). This study aimed to evaluate the effects of PegIFN α-2b on growth and thyroid function in young children with CHB. METHODS A retrospective study was performed by extracting clinical data from children with CHB who received PegIFN α-2b monotherapy at the Public Health Clinical Center of Chengdu between June 2017 and December 2020. Mean, SD, independent samples t test and 1-way repeated analysis of variance were used to evaluate relevant data. RESULTS A total of 62 children were included in this study. Overall, significant differences were observed in the weight-for-age z score (WAZ), height-for-age z score (HAZ) and body mass index-for-age z score (BAZ) at different time points ( P < 0.001). WAZ, HAZ and BAZ were not affected by PegIFN α-2b at 24 weeks of treatment (all P > 0.05). WAZ, HAZ and BAZ at the end of treatment and 48 weeks after treatment; WAZ at 96 weeks after treatment were lower than baseline levels (all P < 0.05). No statistical differences were found in HAZ and BAZ at 96 weeks after treatment compared with baseline. Thyroid dysfunction developed in 17.7% of children during the treatment. Thyroid dysfunction was transient and had no effect on growth. CONCLUSIONS PegIFN α-2b has inhibitory effects on growth and can increase the incidence of thyroid dysfunction in young children with CHB. These effects are generally reversible with the cessation of therapy, although WAZ had not returned to baseline after 96 weeks of observation.
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Affiliation(s)
- Qiufeng He
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Chuangjie Mao
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Zhili Chen
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Fangfang Duan
- Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Liang Huang
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Rong Hu
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Yang Deng
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
| | - Jun Cheng
- Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Song Yang
- Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yilan Zeng
- From the Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China
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Gan Y, Zhang H. Functional cure of a young child with chronic hepatitis B cirrhosis treated by pegylated interferon α combination therapy: A case report. Medicine (Baltimore) 2025; 104:e41103. [PMID: 39792754 PMCID: PMC11729262 DOI: 10.1097/md.0000000000041103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/09/2024] [Indexed: 01/12/2025] Open
Abstract
RATIONALE Current research on antiviral treatment in children is relatively limited, especially in children under 1 year old. PATIENT CONCERNS Liu XX, an 8-month-old infant (case number: 3001120473), presented to the hospital in August 2016 with a chief complaint of being "hepatitis B surface antigen positive for 8 months and experiencing abnormal liver function for 5 months." DIAGNOSES The patient was diagnosed as chronic hepatitis B cirrhosis (G3S3-4) with active compensatory phase. INTERVENTIONS The treatment regimen commenced with lamivudine (LAM) for the initial 8 weeks, followed by the addition of interferon α (IFNα) after 1 year of age. At 2 years old, LAM was substituted with entecavir, and at 3 years old, IFNα was replaced with pegylated interferon α (PEG IFNα). OUTCOMES After 8 weeks of LAM monotherapy, Liu XX experienced hepatitis B e antigen loss. Subsequently, after 36 weeks of IFNα add-on therapy, hepatitis B virus DNA became undetectable, and after 48 weeks of switching to PEG IFNα treatment, hepatitis B surface antigen loss was observed. Remarkably, following 50 weeks of drug discontinuation, the child remained functionally cured. LESSONS Chronic hepatitis B virus-infected infants and young children can achieve durable functional cure with PEG IFNα-based individualized therapy. This case provides a valuable reference for the diagnosis and treatment of such patients.
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Affiliation(s)
- Yu Gan
- Pediatric Hepatology, Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Hongfei Zhang
- Jumei Doctor Group Medical (Shenzhen) Co., Ltd, Shenzhen, China
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Matsubara T, Hagiwara S, Nishida N, Omaru N, Yoshida A, Yamamoto T, Komeda Y, Takenaka M, Kudo M. Observational pilot study of switching from entecavir to tenofovir alafenamide in patients with chronic hepatitis B. Sci Rep 2025; 15:869. [PMID: 39757251 PMCID: PMC11701118 DOI: 10.1038/s41598-025-85317-3] [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: 09/21/2024] [Accepted: 01/01/2025] [Indexed: 01/07/2025] Open
Abstract
This study evaluated the long-term efficacy and safety of the widely used drugs entecavir (ETV) and tenofovir alafenamide (TAF), as well as the incidence of HCC.A nonrandomized, prospective, observational analysis included 77 patients with chronic hepatitis B who were assigned to continue ETV or switch TAF. After 240 weeks, the mean changes in serum hepatitis B surface antigen (- 0.365 ± 0.069 log IU/mL vs. 0.301 ± 0.039 log IU/mL, p = 0.39) and hepatitis B core-related antigen (- 0.215 ± 0.092 log IU/mL vs. - 0.195 ± 0.056 log IU/mL) were not significantly different between the ETV and TAF groups. There were also no differences between the two groups in estimated glomerular filtration rate (- 5.407 ± 1.660 vs. - 2.666 ± 1.52, p = 0.240), urinary β2-microglobulin β/creatinine (ETV: 2.330 ± 0.374 at baseline and 2.335 ± 0.257 at 240 weeks; TAF: 2.720 ± 0.073 and 2.123 ± 0.310, p = 0.996 and 0.455, respectively) or urinary N-acetyl-β-D-glucosaminidase/creatinine (ETV: 0.040 ± 0.005 at baseline and 0.044 ± 0.004 at 240 weeks; TAF: 0.049 ± 0.005 and 0.053 ± 0.005, p = 0.642 and 0.684, respectively). Finally, no significant difference was found in the incidence of HCC between the ETV and TAF groups (log-rank test, p = 0.08). In conclusion, the long-term observation of this study demonstrated that ETV and TAF have comparable efficacy and safety.Clinical trial registration: UMIN000026465.
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Affiliation(s)
- Takuya Matsubara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan.
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Naoya Omaru
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Akihiro Yoshida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Tomoki Yamamoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Mamoru Takenaka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka- Sayama, Osaka, 589-8511, Japan
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Huang C, Lu Y, Wang Z, Jiang Q, Dong Y, Cao L, Yan J, Xu Z, Wang F, Gao Y, Fu J, Zhang M, Wang FS. Correlation Between Clinical Indicators and Liver Pathology in Children with Chronic Hepatitis B. Biomedicines 2024; 12:2903. [PMID: 39767809 PMCID: PMC11726914 DOI: 10.3390/biomedicines12122903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/13/2024] [Accepted: 12/18/2024] [Indexed: 01/05/2025] Open
Abstract
Background: Chronic hepatitis B (CHB) in children presents a significant global health challenge, with liver inflammation and fibrosis being critical concerns for disease progression and long-term outcomes. Methods: This retrospective study analyzed 1629 pediatric CHB patients from the Fifth Medical Center of Chinese PLA General Hospital, spanning from January 2000 to December 2021. Liver biopsies were performed to assess the severity of liver inflammation and fibrosis, which were graded using the Scheuer scoring system. Key clinical indicators, including age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), were evaluated for their predictive value in determining disease severity using restricted cubic spline regression models. Results: Significant nonlinear associations were found between the clinical indicators and liver pathology. Older age was strongly associated with increased risks of moderate to severe inflammation (OR 2.21, 95% CI: 1.34-3.63, p = 0.002) and significant fibrosis (OR 2.22, 95% CI: 1.31-3.77, p = 0.003). Elevated ALT levels (≥80 U/L) were correlated with a higher likelihood of moderate to severe inflammation (OR 1.82, 95% CI: 1.05-3.15, p = 0.033), while higher GGT levels (≥50 U/L) were significantly associated with advanced fibrosis (OR 2.62, 95% CI: 1.72-3.99, p < 0.001). Conclusions: Regular monitoring of clinical indicators such as ALT, AST, and GGT levels plays a critical role in identifying pediatric CHB patients at higher risk of moderate to severe inflammation and significant fibrosis. Our findings highlight the value of integrating age and key biochemical markers into non-invasive diagnostic algorithms for the early detection and management of liver pathology in children.
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Affiliation(s)
- Chenyang Huang
- Medical School of Chinese PLA, Beijing 100853, China;
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Ying Lu
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100010, China; (Y.L.); (Z.X.); (F.W.); (Y.G.)
| | - Ziwei Wang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Qiyu Jiang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Yi Dong
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Lili Cao
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Jianguo Yan
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Zhiqiang Xu
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100010, China; (Y.L.); (Z.X.); (F.W.); (Y.G.)
| | - Fuchuan Wang
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100010, China; (Y.L.); (Z.X.); (F.W.); (Y.G.)
| | - Yinjie Gao
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100010, China; (Y.L.); (Z.X.); (F.W.); (Y.G.)
| | - Junliang Fu
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Min Zhang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
| | - Fu-Sheng Wang
- Medical School of Chinese PLA, Beijing 100853, China;
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing 100039, China; (Z.W.); (Q.J.); (Y.D.); (L.C.); (J.Y.); (J.F.)
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Mutimer D, Atabani SF, Brown M, Logan J, Kelgeri C. Determinants of HBeAg loss during follow-up of a multiethnic pediatric cohort. J Med Virol 2024; 96:e29936. [PMID: 39323085 DOI: 10.1002/jmv.29936] [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: 05/21/2024] [Revised: 08/19/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
Hepatitis B e antigen (HBeAg) loss is a key event in the natural history of chronic hepatitis B virus infection. The rate and determinants of HBeAg loss depend upon cohort characteristics at baseline. Few studies have examined the age-dependent rate, and none have examined the effect of patient sex and ethnicity on the age-dependant rate. The study of age-dependent rates requires the identification and long-term follow-up of a pediatric cohort. We have studied the age-dependent rate of HBeAg loss, and the rate of HBeAg loss measured from baseline, in a multi-ethnic cohort of 454 pediatric patients. During observation, HBeAg loss was observed in 121/303 (39.9%) HBeAg-positive patients. The rate of HBeAg loss was greater in the second versus the first and third decades of life. The age-related rate of HBeAg loss was clearly affected by patient sex and ethnicity, with earlier loss observed for males and for White versus both South Asian and Chinese ethnicities. When measured from baseline, Chinese patients had a slower rate of HBeAg loss in comparison with White patients. In multivariate analysis of HBeAg loss during prolonged follow-up, male sex, older age, and White ethnicity were associated with HBeAg loss, but antiviral treatment was not.
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Affiliation(s)
- David Mutimer
- Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, England
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, England
| | - Sowsan F Atabani
- United Kingdom Health Security Agency (UKHSA), Birmingham, UK
- Virology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, England
| | - Maxine Brown
- Liver Unit, Birmingham Children's Hospital, Birmingham, England
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Zeng QL, Chen RY, Lv XY, Huang S, Li WZ, Pan YJ, Wang FS, Yu ZJ. Functional cure induced by tenofovir alafenamide plus peginterferon-alpha-2b in young children with chronic hepatitis B: a case series study. BMC Infect Dis 2024; 24:830. [PMID: 39148030 PMCID: PMC11325612 DOI: 10.1186/s12879-024-09723-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 08/06/2024] [Indexed: 08/17/2024] Open
Abstract
BACKGROUND AND AIMS Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.
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Affiliation(s)
- Qing-Lei Zeng
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Ru-Yue Chen
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xue-Yan Lv
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Shuo Huang
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Wei-Zhe Li
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Ya-Jie Pan
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
| | - Zu-Jiang Yu
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
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You H, Wang F, Li T, Xu X, Sun Y, Nan Y, Wang G, Hou J, Duan Z, Wei L, Jia J, Zhuang H. Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2022). J Clin Transl Hepatol 2023; 11:1425-1442. [PMID: 37719965 PMCID: PMC10500285 DOI: 10.14218/jcth.2023.00320] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 09/19/2023] Open
Abstract
To facilitate the achieving of the goal of "eliminating viral hepatitis as a major public health threat by 2030" set by the World Health Organization, the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases (both are branches of the Chinese Medical Association) organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China (version 2022). With the support of available evidence, this revision of the guidelines focuses on active prevention, large scale testing, and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B related disease burden.
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Affiliation(s)
- Hong You
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fusheng Wang
- The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Taisheng Li
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoyuan Xu
- Peking University First Hospital, Beijing, China
| | - Yameng Sun
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yuemin Nan
- Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | | | - Jinlin Hou
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongping Duan
- Beijing You-An Hospital, Capital Medical University, Beijing, China
| | - Lai Wei
- Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hui Zhuang
- Peking University Health Science Center, Beijing, China
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Wang Y, Guo L, Shi J, Li J, Wen Y, Gu G, Cui J, Feng C, Jiang M, Fan Q, Tang J, Chen S, Zhang J, Zheng X, Pan M, Li X, Sun Y, Zhang Z, Li X, Hu F, Zhang L, Tang X, Li F. Interferon stimulated immune profile changes in a humanized mouse model of HBV infection. Nat Commun 2023; 14:7393. [PMID: 37968364 PMCID: PMC10652013 DOI: 10.1038/s41467-023-43078-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 10/30/2023] [Indexed: 11/17/2023] Open
Abstract
The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.
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Affiliation(s)
- Yaping Wang
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Liliangzi Guo
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Jingrong Shi
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Jingyun Li
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yanling Wen
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Guoming Gu
- Guangzhou XY Biotechnology Co., Ltd, Room 2048, Building 1, No. 6, Nanjiang Second Road, Pearl River Street, Nansha District, Guangzhou, China
| | - Jianping Cui
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Chengqian Feng
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Mengling Jiang
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Qinghong Fan
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Jingyan Tang
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Sisi Chen
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Jun Zhang
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Xiaowen Zheng
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Meifang Pan
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Xinnian Li
- Guangzhou Forevergen Medical Laboratory, Room 802, No. 8, Luoxuan 3rd Road, Haizhu, Guangzhou, Guangdong, China
| | - Yanxia Sun
- Cytek (Shanghai) Biosciences Co, Ltd, Guangzhou, China
| | - Zheng Zhang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Xian Li
- Guangzhou XY Biotechnology Co., Ltd, Room 2048, Building 1, No. 6, Nanjiang Second Road, Pearl River Street, Nansha District, Guangzhou, China
| | - Fengyu Hu
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China
| | - Liguo Zhang
- CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xiaoping Tang
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China.
| | - Feng Li
- Institute of infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, 8 Huaying Road, Baiyun District, Guangzhou, Guangdong Province, China.
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Zhou J, He X, Ou Y, Peng S, Li D, Zhou Q, Fu J, Long Y, Tan Y. Role of CXCR5 + CD8 + T cells in human hepatitis B virus infection. J Viral Hepat 2023; 30:638-645. [PMID: 37129474 DOI: 10.1111/jvh.13840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/05/2023] [Accepted: 04/15/2023] [Indexed: 05/03/2023]
Abstract
The replication of HBV in hepatocytes can be effectively inhibited by lifelong antiviral therapy. Because of the long-term presence of HBV reservoirs, the virus rebound frequently occurs once the treatment is stopped, which poses a considerable obstacle to the complete removal of the virus. In terms of gene composition, regulation of B cell action and function, CXCR5+ CD8+ T cells are similar to CXCR5+ CD4+ T follicular helper cells, while these cells are characterized by elevated programmed cell death 1 and cytotoxic-related proteins. CXCR5+ CD8+ T cells are strongly associated with progression in inflammatory and autoimmune diseases. In addition, CXCR5 expression on the surface of CD8+ T cells is mostly an indicator of memory stem cell-like failure in progenitor cells in cancer that are more responsive to immune checkpoint blocking therapy. Furthermore, the phenomena have also been demonstrated in some viral infections, highlighting the duality of the cellular immune response of CXCR5+ CD8+ T cells. This mini-review will focus on the function of CXCR5+ CD8+ T cells in HBV infection and discuss the function of these CD8+ T cells and the potential of associated co-stimulators or cytokines in HBV therapeutic strategies.
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Affiliation(s)
- Juan Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Xiaojing He
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yangjing Ou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Shuang Peng
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Dan Li
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Qing Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Jingli Fu
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yunzhu Long
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yingzheng Tan
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
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Yao N, Wang J, Wu Y, Zhu Y, Feng Y, Fu S, Liu J, Yang Y, Zhao Y, Shi L, Yang N, Chen T. Frequent alanine aminotransferase flares and promising antiviral therapy efficacy during the preschool age: An opportunity to achieve HBsAg loss in children with mother-to-child transmitted hepatitis B. J Viral Hepat 2022; 29:748-755. [PMID: 35722733 DOI: 10.1111/jvh.13720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/25/2022] [Accepted: 06/07/2022] [Indexed: 12/09/2022]
Abstract
Alanine aminotransferase (ALT) flare remains one of the determinants of initiating antiviral therapy in children with chronic hepatitis B (CHB). Insufficient data exist regarding children with CHB attributed to mother-to-child transmission. This study aimed to assess the occurrence of spontaneous ALT flares and identify factors affecting therapy-induced hepatitis B surface antigen (HBsAg) loss in the flare cohort. We retrospectively included untreated children with mother-to-child transmitted CHB. The primary outcomes were spontaneous ALT flares and therapy-induced HBsAg loss. Among 83 untreated children, 73.5% (61/83) experienced spontaneous ALT flares during the median follow-up of 14.6 months (range, 0.1-177.1 months), with 54.1% of the first ALT flares and 44.3% of ALT peaks occurring within 6 years of age. Thirty-six of 61 children with ALT flares received antiviral therapy, nine (25.0%) of whom achieved therapy-induced HBsAg loss with a median duration of 19.3 months (range, 6.5-56.2 months). The age of initiation of antiviral therapy was the sole predictor of therapy-induced HBsAg loss (HR = 0.544, 95% CI 0.353-0.838, p = 0.006). The restricted cubic spline showed a negative relationship between the age of initiation of antiviral therapy and HBsAg loss and identified that 6.2 years of age discriminated children with therapy-induced HBsAg loss. Kaplan-Meier estimations suggested a higher probability of HBsAg loss in children who started antiviral therapy before 6.2 years old (p = 0.03). In conclusion, asymptomatic ALT flares were frequent in preschool-aged children with mother-to-child transmitted CHB, and early initiation of antiviral therapy showed promising effects in those children with ALT flares.
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Affiliation(s)
- Naijuan Yao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jia Wang
- Department of Infectious Diseases, The Eighth Hospital of Xi'an, Xi'an, Shaanxi, China
| | - Yuchao Wu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yage Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yali Feng
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shan Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jinfeng Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuan Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yingren Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lei Shi
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Nan Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Tianyan Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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11
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He Y, Zhou Y, Wang H, Peng X, Chang Y, Hu P, Ren H, Xu H. The efficacy of pegylated interferon alpha-2a and entecavir in HBeAg-positive children and adolescents with chronic hepatitis B. BMC Pediatr 2022; 22:426. [PMID: 35854256 PMCID: PMC9297582 DOI: 10.1186/s12887-022-03482-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background and objectives Pegylated interferon alpha-2a (peg-IFN α-2a) and entecavir (ETV) are both recommended as the first-line antiviral drugs for chronic hepatitis B (CHB) at present. We aimed to compare the efficacy and safety between peg-IFN α-2a and ETV initial therapy in children and adolescents with CHB and investigate the potential factors affecting the treatment response during the first 48 weeks. Methods We retrospectively selected 70 treatment-naïve children and adolescents with CHB who received peg-IFN α-2a(n = 26) or ETV(n = 44) as initial therapy and completed 48-week follow-up for data analysis. Blood samples before treatment were collected from 26 patients of the cohort to assess the cytokine profiles. Results We found that initial peg-IFN therapy results in higher rates of hepatitis B surface antigen (HBsAg) serological response (SR) but lower rates of virological and biochemical response rates compared to ETV at week 48. As for achieving hepatitis B e antigen (HBeAg) SR, peg-IFN was comparable to ETV in the univariate analysis and turned out to be better than ETV after adjustment for important baseline factors. We also found that elevated pre-treatment IL-18 level was significantly associated with HBeAg SR, and remained as the only independent factor of predicting HBeAg SR after adjustment for other important factors. No serious adverse effects of the 2 drugs were reported during the 48-week follow-up. Conclusions comparing to ETV, peg-IFN was superior in achieving HBsAg and HBeAg SR; higher baseline IL-18 levels were independently associated with HBeAg SR in this study of children and adolescents with CHB. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-022-03482-0.
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Affiliation(s)
- Yi He
- Department of Infection, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, 136, Zhongshan Road, Yuzhong District, Chongqing, 400014, People's Republic of China
| | - Yingzhi Zhou
- Department of Infection, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, 136, Zhongshan Road, Yuzhong District, Chongqing, 400014, People's Republic of China
| | - Huimin Wang
- Department of Infection, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, 136, Zhongshan Road, Yuzhong District, Chongqing, 400014, People's Republic of China
| | - Xiaorong Peng
- Department of Infection, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, 136, Zhongshan Road, Yuzhong District, Chongqing, 400014, People's Republic of China
| | - Yunan Chang
- Department of Infection, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, 136, Zhongshan Road, Yuzhong District, Chongqing, 400014, People's Republic of China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Hongmei Xu
- Department of Infection, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, 136, Zhongshan Road, Yuzhong District, Chongqing, 400014, People's Republic of China.
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12
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Pan J, Wang H, Yao T, Liao X, Cheng H, Liangpunsakul S, Wang Y, Zhang M, Zhang Z. Clinical Predictors of Functional Cure in Children 1-6 Years-old with Chronic Hepatitis B. J Clin Transl Hepatol 2022; 10:405-411. [PMID: 35836765 PMCID: PMC9240240 DOI: 10.14218/jcth.2021.00142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/31/2021] [Accepted: 09/15/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Hepatitis B surface antigen (HBsAg) clearance is significantly more common in children with chronic hepatitis B (CHB) than in adults; however, the possible influencing factors related to HBsAg loss have yet to be found. This study aimed to explore the efficacy of long-term interferon (IFN)α therapy in treating children with CHB and analyzed the factors influencing functional cure after treatment. METHODS A total of 236 children aged 1-6 years and diagnosed with CHB via liver biopsy were included in the study, all receiving IFNα treatment (IFNα-2b monotherapy, IFNα-2b followed by lamivudine [LAM] or IFNα-2b combined with LAM) and followed up for 144 weeks. A comprehensive analysis was conducted on clinical data, including biochemical items, serum markers of hepatitis B virus (HBV) and immunological indexes, and logistic regression analysis was used to screen the influencing factors related to HBsAg loss. RESULTS The cumulative loss rates of HBsAg were 79.5%, 62.1% and 42.1% at 144 weeks after the start of treatment in the 1-3 years-old group, 3-5 years-old group and 5-7 years-old group, respectively (p<0.05). IFNα-2b combined with LAM treatment displayed the highest HBsAg loss rates compared with monotherapy and sequential treatment (p=0.011). Younger baseline age and lower HBsAg levels were independent factors for the prediction of HBsAg loss (p<0.05). The baseline PreS1 and hepatitis B core antibody levels in the HBsAg loss group were lower than those in the HBsAg non-loss group. In addition, the PreS1 level was positively corelated with the level of HBsAg, HBV DNA and liver inflammation. CONCLUSIONS Long-term treatment with IFNα was effective in achieving HBsAg loss in CHB children aged 1-6 years-old. Age less than 3 years-old and lower HBsAg levels are independent predictors of functional cure in children with CHB.
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Affiliation(s)
- Jing Pan
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
- Liver Disease Department of The Fifth Medical Center of the General Hospital of PLA, Beijing, China
| | - Haiyan Wang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Tiantian Yao
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
| | - Xuejiao Liao
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Hao Cheng
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine; Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA
| | - Yan Wang
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
| | - Min Zhang
- Liver Disease Department of The Fifth Medical Center of the General Hospital of PLA, Beijing, China
- Correspondence to: Zheng Zhang, Institute of Hepatology, Shenzhen 3 People’s Hospital, Shenzhen, Guangdong 518112, China. ORCID: https://orcid.org/0000-0002-3544-1389. Tel/Fax: +86-755-8123-8983, E-mail: ; Min Zhang, Liver Disease Department of The Fifth Medical Center of the General Hospital of PLA, 100 Western 4 Ring Middle Road, Beijing 100039, China. Tel/Fax: +86-10-6693-3129, E-mail:
| | - Zheng Zhang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital; The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
- Correspondence to: Zheng Zhang, Institute of Hepatology, Shenzhen 3 People’s Hospital, Shenzhen, Guangdong 518112, China. ORCID: https://orcid.org/0000-0002-3544-1389. Tel/Fax: +86-755-8123-8983, E-mail: ; Min Zhang, Liver Disease Department of The Fifth Medical Center of the General Hospital of PLA, 100 Western 4 Ring Middle Road, Beijing 100039, China. Tel/Fax: +86-10-6693-3129, E-mail:
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13
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Li Y, Xiao Y, Li L, Song Y, Zhai X, Liu J, Duan Z, Yan L, Ding F, Liu J, Zhu L, Jiang J, Zou H, Li L, Liang C, Wang J, Li J. The dynamic changes of HBV quasispecies diversity in infancy after immunoprophylaxis failure: a prospective cohort study. Virol J 2021; 18:236. [PMID: 34844612 PMCID: PMC8628401 DOI: 10.1186/s12985-021-01707-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Previous works have observed that younger infants with chronic hepatitis B virus (HBV) infection are more responsive to antiviral treatment. However, the underlying mechanism remains unclear. In this study, the dynamic changes of HBV quasispecies in infants with immunoprophylaxis failure were investigated to provide virological explanations for clinical management on infantile antiviral therapy. METHODS Thirteen 7-month-old infants with immunoprophylaxis failure and their mothers were enrolled from a prospective cohort, and 8 of them were followed up to 3 years old. The sequences of HBV quasispecies were analyzed by the full-length genome clone-based sequencing, and compared among mothers and their infants at different ages. RESULTS The results revealed that the complexity, mutation frequency and genetic distance of HBV quasispecies decreased significantly at full-length, partial open reading frames and regulatory regions of HBV genome at nucleotide level in 7-month-old infants comparing with their mothers, whereas increased significantly to near the maternal level when infants grew up to 3 years old. Furthermore, similar changes were also found in Core, PreS2, RT and P regions of HBV genome at amino acid level, especially for potential NAs-resistant mutants in RT region and immune-escape mutants in Core and PreS2 regions. CONCLUSIONS This study uncovered the evolution of HBV quasispecies in infancy after mother-to-child transmission, which may provide the virological evidence for explaning that younger children are more responsive to antiviral therapy.
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Affiliation(s)
- Yi Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Yiwei Xiao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Lili Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Yarong Song
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Xiangjun Zhai
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, China
| | - Jianxun Liu
- Zhengzhou Municipal Center for Disease Control and Prevention, Zhengzhou, 450053, China
| | - Zhongping Duan
- Beijing Youan Hospital, Capital Medical University, Beijing, 100054, China
| | - Ling Yan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Feng Ding
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Jia Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China
| | - Liguo Zhu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, China
| | - Jie Jiang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, China
| | - Huaibin Zou
- Beijing Youan Hospital, Capital Medical University, Beijing, 100054, China
| | - Lingxiang Li
- Gongyi City Maternal and Child Health Hospital, Zhengzhou, 451200, China
| | - Caihong Liang
- Zhongmu County Maternal and Child Health Hospital, Zhengzhou, 451450, China
| | - Jie Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China.
| | - Jie Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100083, China.
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14
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Wang L, Zhao J, Liu J, Zhen C, Zhang M, Dong Y, Gan Y, Xu Z, Li Y, Zhu S, Wang FS. Long-term benefits of interferon-α therapy in children with HBeAg-positive immune-active chronic hepatitis B. J Viral Hepat 2021; 28:1554-1562. [PMID: 34448324 DOI: 10.1111/jvh.13598] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 07/10/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
The long-term benefits of interferon-α (IFN-α) treatment in children with chronic hepatitis B (CHB) remain unclear. We conducted a retrospective and real-world study to evaluate the safety and long-term clearance rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in CHB children who received IFN-α monotherapy for 72 weeks and were with 13-year follow-up visit. Participants treated with IFN-α (n = 316) were more likely to become HBeAg negatve (39.87% vs. 27.37%; p < .05) and HBsAg negative (11.08% vs. 3.16%; p < .05) by the end of the treatment period than untreated participants (n = 95). Treated participants also had higher cumulative rates of HBeAg loss (74.13% vs. 59.27%; p < .05) and HBsAg loss (46.95 vs. 33.11%; p < 0.05) than untreated participants in parallel by the end of 13-year follow-up. In particular, the cumulative rate of HBsAg loss was higher in treated children aged 1-7 years than in those aged 8-17 years (71.40% vs. 39.0%; p < .01). Children who were HBeAg-negative at the end of IFN-α treatment or who had serum alanine aminotransferase levels of ≥80 IU/L at baseline were likely to have higher cumulative HBsAg loss rates. Accordingly, HBeAg loss at 72 weeks was positively associated with the cumulative HBsAg loss rate in untreated children. There were no serious adverse events of IFN-α therapy for the treated patients throughout the study period. Overall, IFN-α therapy was effective in obtaining higher long-term cumulative rates of HBeAg and HBsAg loss in children with HBeAg-positive immune-active CHB, especially among those aged 1-7 years.
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Affiliation(s)
- Limin Wang
- Medical School of Chinese PLA, China.,Department of Live disease, Fifth Medical Center of Chinese, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jinfang Zhao
- Department of Infectious Disease, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jiaye Liu
- Department of Infectious Disease, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Cheng Zhen
- Department of Infectious Disease, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Min Zhang
- Department of Live disease, Fifth Medical Center of Chinese, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Yi Dong
- Department of Live disease, Fifth Medical Center of Chinese, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Yu Gan
- Department of Live disease, Fifth Medical Center of Chinese, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zhiqiang Xu
- Department of Live disease, Fifth Medical Center of Chinese, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Yuanyuan Li
- Department of Infectious Disease, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Shishu Zhu
- Department of Live disease, Fifth Medical Center of Chinese, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Fu-Sheng Wang
- Medical School of Chinese PLA, China.,Department of Infectious Disease, Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
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15
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Wang G, Duan Z. Guidelines for Prevention and Treatment of Chronic Hepatitis B. J Clin Transl Hepatol 2021; 9:769-791. [PMID: 34722192 PMCID: PMC8516840 DOI: 10.14218/jcth.2021.00209] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/20/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
To achieve the goal of the World Health Organization to eliminate viral hepatitis as a major public health threat by 2030, the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology convened an expert panel in 2019 to update the guidelines for the prevention and treatment of chronic hepatitis B (CHB). The current guidelines cover recent advances in basic, clinical, and preventive studies of CHB infection and consider the actual situation in China. These guidelines are intended to provide support for the prevention, diagnosis, and treatment of CHB.
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Affiliation(s)
- Guiqiang Wang
- Center for Liver Diseases, Department of Infectious Diseases, Peking University First Hospital; Department of Infectious and Liver Diseases, Peking University International Hospital, Beijing, China
| | - Zhongping Duan
- Center for Difficult and Complicated Liver Diseases and Artificial Liver, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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16
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Stinco M, Rubino C, Trapani S, Indolfi G. Treatment of hepatitis B virus infection in children and adolescents. World J Gastroenterol 2021; 27:6053-6063. [PMID: 34629819 PMCID: PMC8476329 DOI: 10.3748/wjg.v27.i36.6053] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/30/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one of the main causes of morbidity and mortality worldwide. Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection, with normal or only slightly raised aminotransferases. Although a conservative approach in children is usually recommended, different therapies exist and different therapeutic approaches are possible. The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma, although these complications are rare in children. Both United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) have approved interferon alfa-2b for children aged 1 year and older, pegylated interferon alfa-2a and lamivudine for children aged 3 years and older, entecavir for use in children aged 2 years and older, and adefovir for use in those 12 years of age and older. Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by US-FDA for treatment in children aged 12 years and older. Finally, EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age. This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.
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Affiliation(s)
- Mariangela Stinco
- Department of Health Sciences, Pediatric Section, Meyer Children’s University Hospital, Florence 50139, Italy
| | - Chiara Rubino
- Department of Health Sciences, Pediatric Section, Meyer Children’s University Hospital, Florence 50139, Italy
| | - Sandra Trapani
- Department of Health Sciences, Pediatric Section, Meyer Children’s University Hospital, Florence 50139, Italy
| | - Giuseppe Indolfi
- Department Neurofarba, University of Florence and Meyer Children’s University Hospital, Florence 50139, Italy
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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: 36] [Impact Index Per Article: 9.0] [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
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18
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Nicastro E, Norsa L, Di Giorgio A, Indolfi G, D'Antiga L. Breakthroughs and challenges in the management of pediatric viral hepatitis. World J Gastroenterol 2021; 27:2474-2494. [PMID: 34092970 PMCID: PMC8160618 DOI: 10.3748/wjg.v27.i20.2474] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/04/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) major causes of advanced liver disease and mortality worldwide. Although regarded as benign infections in children, their persistence through adulthood is undoubtedly of concern. Recent advances in HCV treatment have restored the visibility of these conditions and raised expectations for HBV treatment, which is currently far from being curative. Herein we describe direct-acting antivirals available for pediatric HCV (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) and their real-world use. A critical review of the HBV pediatric classification is provided. Anti-HBV investigational compounds are reviewed in light of the pathophysiology in the pediatric population, including capsid assembly modulators, antigen secretion inhibitors, silencing RNAs, and immune modifiers. Recommendations for screening and management of immunosuppressed children or those with other risk factors or comorbidities are also summarized.
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Affiliation(s)
- Emanuele Nicastro
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Lorenzo Norsa
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Angelo Di Giorgio
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Giuseppe Indolfi
- Department of Neurofarba, Meyer Children's University Hospital of Florence, Florence 50137, Italy
| | - Lorenzo D'Antiga
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
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19
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Yang Y, Huang A, Zhao Y. Spontaneous loss of chronic HBV infection markers in treatment-naïve children: a systematic review and pooled meta-analyses. Expert Rev Anti Infect Ther 2021; 19:649-660. [PMID: 33164585 DOI: 10.1080/14787210.2021.1845652] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/30/2020] [Indexed: 12/24/2022]
Abstract
Objectives: Chronicity could be a serious threat to hepatitis B virus (HBV)-infected children. The necessity of antiviral treatment to HBV-infected children has caused much controversy. The authors aimed to conduct a systematic review and meta-analysis of synthesized evidence regarding the spontaneous loss of chronic HBV infection markers in treatment-naïve children for exploring their long-term management.Methods: Observational cohort studies and non-treatment arms of randomized controlled trials were searched that reported the spontaneous loss of chronic HBV infection markers in untreated children (characterized by the presence of HBsAg ≥6-month), via the rates of hepatitis B surface antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) seroconversion, and HBV DNA suppression with random-effects model.Results: Of 7,427 studies screened, 20 were included in meta-analysis. With cumulative 23,153 person-years of follow-up, the pooled annual incidences of HBsAg and HBeAg loss, HBV DNA suppression were 1, 6, 7%, respectively. Rates within HBeAg loss and HBV DNA suppression did differ by the transmission modes and ALT levels, not in HBsAg.Conclusion: Spontaneous HBsAg loss (function cure) occurs infrequently in treatment-naïve children with chronic HBV infection. Design of practically applicable programs aiming at therapeutics of children may be necessary to support the goal of eliminating HBV infection worldwide.
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Affiliation(s)
- Yuting Yang
- National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ailong Huang
- Institute for Viral Hepatitis, Ministry of Education Key Laboratory of Molecular Biology on Infectious Diseases, Chongqing Medical University, Chongqing, China
| | - Yao Zhao
- National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
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20
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Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure. Viruses 2021; 13:v13050745. [PMID: 33922828 PMCID: PMC8146791 DOI: 10.3390/v13050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.
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21
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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.
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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
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22
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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23
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Efficacy and Safety of Pegylated Interferon for the Treatment of Chronic Hepatitis B in Children and Adolescents: A Systematic Review and Meta-analysis. Pediatr Infect Dis J 2020; 39:1121-1126. [PMID: 32858647 DOI: 10.1097/inf.0000000000002876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Pegylated interferon (PEG-IFN) has recently been approved for the treatment of chronic hepatitis B in children and adolescents. However, the exact efficacy and safety remains to be confirmed. OBJECTIVES A systematic review and meta-analysis was performed to assess the efficacy and safety of PEG-IFN for the treatment of chronic hepatitis B in children and adolescents. METHODS Databases including MEDLINE/PubMed, Ovid-EMbase, the Cochrane Library and China National Knowledge Internet were searched to collect clinical trials examining the efficacy and safety of PEG-IFN in children and adolescents with confirmed hepatitis B virus infection. Data for treatment response, relapse, treatment discontinuations and adverse events were extracted and summarized. RESULTS A total of 10 clinical trials involving 658 patients were identified. Results indicate that 43% (95% confidence interval [CI]: 25%-61%) of the subjects treated with PEG-IFN achieved HBeAg serologic response, 18% (95% CI: 6%-35%) achieved HBsAg serologic response, 68% (95% CI: 55%-79%) achieved virologic response after the end of treatment and 60% (95% CI: 30%-87%) achieved sustained virologic response. CONCLUSION Current evidence indicates that PEG-IFN is effective in children and adolescents with hepatitis B virus and that treatment discontinuation due to serious adverse events is infrequent.
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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.
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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
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25
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Komatsu H, Inui A, Yoshio S, Kanto T, Umetsu S, Tsunoda T, Fujisawa T. High Dose of Pegylated Interferon for the Treatment of Chronic Hepatitis B in Children Infected With Genotype C. JPGN REPORTS 2020; 1:e005. [PMID: 37206604 PMCID: PMC10191545 DOI: 10.1097/pg9.0000000000000005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/27/2020] [Indexed: 05/21/2023]
Abstract
UNLABELLED Chronic hepatitis B virus (HBV) genotype C infection is unlikely to show a good response to interferon (IFN). However, it is unknown whether a high dose of pegylated IFN (PEG-IFN) treatment would be effective for hepatitis B e antigen (HBeAg)-positive children with chronic HBV genotype C infection. METHODS HBeAg-positive children and adolescents with chronic HBV genotype C infection were eligible for this study. To increase the dose of PEG-IFN, all patients received PEG-IFN-α-2a (180 μg) without dose adjustment on the basis of body surface area for 48 weeks and were followed up for 24 weeks after the completion of treatment. RESULTS Thirteen patients (median age, 9 years) were enrolled prospectively for this study. One patient dropped out, and the remaining 12 patients were evaluated. Of the 12 patients, 11 received PEG-IFN of 180 μg/1.73 m2 or more (median, 287 μg/1.73 m2). Eight (67%) experienced HBeAg seroconversion, and 1 (8%) achieved hepatitis B surface antigen (HBsAg) loss at the end of follow-up. There was a significant difference in the decrease of hepatitis B surface antigen levels from the baseline to week 24 of treatment between the responders and the nonresponders. Serum cytokines and chemokines were measured in 10 patients. The levels of C-X-C motif chemokine ligand 9, 10, 11, and 13 in the responders tended to be higher than those in the nonresponders during the first 24 weeks of treatment. CONCLUSIONS A high dose of PEG-IFN treatment was effective and safe. A decrease in the hepatitis B surface antigen level from baseline to week 24 of treatment might be a predictor of HBeAg seroconversion.
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Affiliation(s)
- Haruki Komatsu
- From the Department of Pediatrics, Sakura Medical Center, Toho University, Chiba, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Sachiyo Yoshio
- Liver Diseases, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Tatsuya Kanto
- Liver Diseases, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Shuichiro Umetsu
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Tomoyuki Tsunoda
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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26
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Liu Y, Shi C, Fan J, Wang B, Li G. Hepatitis B-related glomerulonephritis and optimization of treatment. Expert Rev Gastroenterol Hepatol 2020; 14:113-125. [PMID: 31951758 DOI: 10.1080/17474124.2020.1717948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/15/2020] [Indexed: 02/08/2023]
Abstract
Introduction: Multiple studies have revealed a strong relationship between the development of nephropathy and hepatitis B virus (HBV) infection. The underlying pathogenesis of hepatitis B-related glomerulonephritis (HBV-GN) involves immune complexes, which can be isolated from kidney tissues. Clearance of HBV antigenemia improves renal impairment and proteinuria in HBV-GN patients.Areas covered: In this review, we present our current understanding of the epidemiology, pathogenesis, pathology, diagnosis, and treatment of HBV-GN. We discuss the advantages and disadvantages of oral nucleoside/nucleotide analogs (NAs), and the main pharmaceutical treatment for hepatis B.Expert opinion: Currently, antiviral agents are the main HBV-GN therapeutic agents. Although no randomized controlled clinical trials have compared the efficacy of interferon (IFN) and NA, we suggest IFN treatment for pediatric patients (IFN-α in patients ≥1 year; pegIFN-α in patients ≥3 years) considering treatment duration and absence of resistance. Novel NAs have brought about promising treatment options involving high efficacy viral suppression and low resistance rates. NAs with a high barrier to resistance (e.g. entecavir) are recommended as first-line therapy of HBV-GN. Immunosuppression monotherapy, such as corticosteroids, is of little benefit and potentially harmful to HBV-GN patients due to the possibility of viral reactivation.
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Affiliation(s)
- Yanjun Liu
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Cuicui Shi
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Baocan Wang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guangming Li
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Efficacy and safety of interferon alpha-2b versus pegylated interferon alpha-2a monotherapy in children with chronic hepatitis B: a real-life cohort study from Shanghai, China. World J Pediatr 2019; 15:595-600. [PMID: 31487005 DOI: 10.1007/s12519-019-00303-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 08/01/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Interferon alpha (IFN-α) is a preferred therapy for antiviral treatment of children with chronic hepatitis B (CHB) aged > 1 year currently. Peginterferon alpha-2a (Peg-IFN α-2a) is a recommended international guideline for treatment of CHB children, which is limited to children aged > 3 years. But the exact efficacy and safety of IFN-α and Peg-IFN α-2a for treating CHB are not sufficient. METHODS Clinical manifestations, baseline characteristics, related laboratory tests and adverse events were retrospectively analyzed in children with CHB, who visited Children's Hospital of Fudan University and were treated with IFN α-2b or Peg-IFN α-2a monotherapy and followed up from January 2003 to October 2018. RESULTS A total of 36 immune-active patients without advanced fibrosis were enrolled to be treated with IFN α-2b (group A, n = 18) or Peg-IFN α-2a (group B, n = 18). IFN α-2b or Peg-IFN α-2a was administered for a median of 48 weeks subcutaneously by body surface area (BSA) category at a dose of 3 MU/m2 or 104 μg/m2, respectively. HBV e antigen (HBeAg) seroconversion rates at 48 weeks post-treatment were higher in group A than group B (92.9% vs. 87.5%), so as the rates of HBsAg clearance (22.2% vs. 11.1%), and hepatitis B virus (HBV)-DNA < 1000 IU/mL (88.9% vs. 83.3%). Only mild flu-like symptoms and transient neutropenia appeared in some children at the early stage of treatment. No severe abnormal results was observed in other laboratory assessments. CONCLUSION The antiviral monotherapy of 48-week IFN α-2b or Peg-IFN α-2a in children with CHB is well tolerated and effective, which is associated with higher rates of HBeAg seroconversion and HBsAg clearance than in adults and previously pediatric patients.
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Abstract
Introduction: Universal infant hepatitis B virus (HBV) vaccination program has reduced HBV infection dramatically in vaccinated young generations. Management of chronically infected children is still challenging concerning high viral load with mostly mild diseases, yet with a nonnegligible proportion of advanced diseases, and long-term effect of antivirals. However, with more potent antivirals approved for pediatric patients, to start antivirals earlier in eligible patients may benefit their outcomes. This review aimed to update the current management of chronic hepatitis B in children.Areas covered: This review covered the natural history of chronic HBV infection, management of chronic hepatitis B in children from the past to the present, current consensus on the treatment of chronic hepatitis B in children, controversies in cessation of oral antivirals, and management of special populations such as pregnancy and co-infections.Expert opinions: Without contraindication, peginterferon is recommended for immune-active children ≥ 3 years old. For those intolerant, decompensating or preferring oral therapy, first-line Nucleos(t)ide analogs (NUC), Entecavir or Tenofovir, may be applied. For immune-tolerant or inactive carriers, close monitoring is crucial. When to stop NUCs and novel therapies for HBV cure await further research.
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Affiliation(s)
- Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.,Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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Westin J, Aleman S, Castedal M, Duberg AS, Eilard A, Fischler B, Kampmann C, Lindahl K, Lindh M, Norkrans G, Stenmark S, Weiland O, Wejstål R. Management of hepatitis B virus infection, updated Swedish guidelines. Infect Dis (Lond) 2019; 52:1-22. [DOI: 10.1080/23744235.2019.1675903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Johan Westin
- Deparment of Infectious Diseases, Institute of Biomedicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Soo Aleman
- Deparment of Medicine, Division of Infectious Diseases, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Maria Castedal
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ann-Sofi Duberg
- Deparment of Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Anders Eilard
- Deparment of Infectious Diseases, Institute of Biomedicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Björn Fischler
- Deparment of Pediatrics, CLINTEC, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Christian Kampmann
- Deparment of Infectious Diseases, Skåne University Hospital Lund, Lund, Sweden
| | - Karin Lindahl
- Deparment of Medicine, Division of Infectious Diseases, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Magnus Lindh
- Deparment of Infectious Diseases, Institute of Biomedicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Norkrans
- Deparment of Infectious Diseases, Institute of Biomedicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Stephan Stenmark
- Deparment of Clinical Microbiology and Infectious Diseases, Umeå University, Umeå, Sweden
| | - Ola Weiland
- Deparment of Medicine, Division of Infectious Diseases, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Rune Wejstål
- Deparment of Infectious Diseases, Institute of Biomedicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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30
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Hardikar W. Viral hepatitis. J Paediatr Child Health 2019; 55:1038-1043. [PMID: 31317618 DOI: 10.1111/jpc.14562] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/14/2022]
Abstract
Hepatitis viruses A to E can cause abnormal liver function tests in children. Although, overall, they are relatively uncommon in children in Australia, epidemiology diagnosis and treatment modalities for these viruses have evolved over the last decade. This review provides an update on the diagnosis and treatment of viral hepatitis in children.
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Affiliation(s)
- Winita Hardikar
- Department of Gastroenterology, Royal Children's Hospital, Melbourne, Victoria, Australia
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Gao M, Feng C, Ying R, Nie Y, Deng X, Zhu Y, Tang X, Guan Y, Hu F, Li F. A novel one-step quantitative reverse transcription PCR assay for selective amplification of hepatitis B virus pregenomic RNA from a mixture of HBV DNA and RNA in serum. Arch Virol 2019; 164:2683-2690. [PMID: 31428915 DOI: 10.1007/s00705-019-04372-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 07/11/2019] [Indexed: 12/11/2022]
Abstract
Current antiviral therapies against hepatitis B virus (HBV) infections, such as treatment with nucleos(t)ide analogs (NAs) and interferon alpha, can significantly lower HBV DNA titers, eventually to undetectable levels. However, it is still difficult to completely eliminate the stable template of HBV, the covalently closed circular DNA (cccDNA), and this contributes to viral rebound when treatment is discontinued. HBV pregenomic RNA (pgRNA), which was recently found to be present in the enveloped mature HBV viral particle in blood, is tentatively regarded, with still accumulating clinical evidence, as a novel bona fide virological marker reflecting the amount and status of cccDNA when serum HBV DNA becomes undetectable. HBV pgRNA and DNA share almost identical sequences, and it is therefore difficult to differentiate pgRNA from viral DNA using normal PCR methods. To exclude interference from viral DNA, methods for measuring pgRNA usually require a selective DNA degradation step, which is complicated and time-consuming and also compromises the accuracy of detection. In this study, we developed a simplified quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay with improved accuracy achieved by probing the polyA tail of pgRNA. Using clinical serum samples, we observed that not all patients share the same 3' sequence, suggesting slight differences between HBV strains in the way they end transcription. We then designed and evaluated a universal primer and probe set for distinguishing HBV pgRNA from HBV DNA. Our results demonstrated that a one-step qRT-PCR assay could selectively amplify HBV pgRNA from a mixture of HBV RNA and DNA, which is valuable for clinical applications.
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Affiliation(s)
- Ming Gao
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Chengqian Feng
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Ruosu Ying
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Yuan Nie
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Xizi Deng
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Ying Zhu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Xiaoping Tang
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Yujuan Guan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China
| | - Fengyu Hu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China.
| | - Feng Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, 627 Dongfeng Dong Rd, Guangzhou, 510060, Guangdong, China.
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Ning L, Huang X, Xu Y, Yang G, Yang J, Fu Q, Zhang Q, Liu H, Wu X, Wang Z, Luo K. Boosting of Hepatitis B Virus-Specific T Cell Responses After Pegylated-Interferon-α-2a Therapy for Hepatitis B e Antigen-Positive Pediatric Patients. J Interferon Cytokine Res 2019; 39:740-751. [PMID: 31329012 DOI: 10.1089/jir.2019.0042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Treatment of chronic hepatitis B with pegylated-interferon-α-2a (PegIFNα) in pediatric patients can lead to a higher rate of hepatitis B virus (HBV) surface antigen (HBsAg) loss than in adults. However, the mechanism of underlying immune response is not clear. The aim of this study was to explore innate and adaptive immunity, especially HBV-specific T cell responses in hepatitis B e antigen (HBeAg)-positive pediatric patients, who have experienced HBsAg loss. Isolated lymphocytes of 20 HBeAg-positive pediatric patients were collected every 12 weeks until treatment was stopped. The phenotype of T/natural killer (NK) cells and function of HBV-specific T cells were analyzed by flow cytometry. The frequency of CD69 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressed on T cells and TRAIL on CD56hi NK cells in patients with HBsAg loss was remarkably higher compared with nonresponse patients. Furthermore, in vitro peptide stimulation of HBV-specific T cell responses was increased in patients with HBsAg loss when compared with week 0 and 48, and correlated with decline of viral load. The PegIFNα therapy in pediatric patients triggered T/NK cell activation and HBV-specific T cell responses, thereby contributing to successful viral control.
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Affiliation(s)
- Lu Ning
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ying Xu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guifeng Yang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Juncheng Yang
- Office of Prof. Kangxian Luo, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qunfang Fu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qi Zhang
- Office of Prof. Kangxian Luo, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hai Liu
- Office of Prof. Kangxian Luo, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoting Wu
- Office of Prof. Kangxian Luo, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhanhui Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangxian Luo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Fan H, Lin L, Jia S, Xie M, Luo C, Tan X, Ying R, Guan Y, Li F. Interferon alpha treatment leads to a high rate of hepatitis B surface antigen seroconversion in Chinese children with chronic hepatitis B. J Viral Hepat 2019; 26 Suppl 1:77-84. [PMID: 31380586 DOI: 10.1111/jvh.13165] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 05/15/2019] [Indexed: 12/24/2022]
Abstract
Chronic hepatitis B virus (HBV) infection (CHB) in children remains a public health challenge despite significant success in programme is established to prevent mother-to-child transmission. In particular, CHB in Chinese children are mostly acquired through vertical transmission, which differs from the common infection route reported in other countries and regions. This situation has resulted in a high endemic prevalence of CHB in Chinese adults. Thus, successful treatment of children with CHB will prevent the development of advanced liver diseases in late adulthood. However, there is still no consensus on the clinical guideline to treat paediatric CHB. In this study, we evaluated the potential of interferon alpha (IFNa) treatment for Chinese children with CHB. A total of 41 patients with CHB aged 3-17 years were enrolled in this retrospective study: 21 patients were treated with pegylated (PEG)-IFNa and 20 patients without treatment served as the control group. The rates of HBV DNA suppression, hepatitis B e antigen (HBeAg) clearance and hepatitis B surface antigen (HBsAg) clearance were significantly higher in the PEG-IFNa treatment group than in the control group (P < 0.05 at 48 weeks). Unexpectedly, PEG-IFNa treatment achieved a high rate of HBsAb production, far exceeding the clinical outcome in documented PEG-IFNa-treated CHB adults. Further analysis revealed that younger children (3-6 years old) were more responsive to PEG-IFNa treatment with respect to achieving a protective level of HBsAb in a short treatment cycle than adolescents (10-17 years old). Overall, these results indicate that the immune system of children might have a preserved PEG-IFNa-mediated mechanism to completely control HBV, which can help to design new strategies to treat CHB patients.
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Affiliation(s)
- Huimin Fan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Luping Lin
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shijie Jia
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Min Xie
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Chun Luo
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xinghua Tan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ruosu Ying
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yujuan Guan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Feng Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
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Liu Y, Li H, Yan X, Wei J. Long-term efficacy and safety of peginterferon in the treatment of children with HBeAg-positive chronic hepatitis B. J Viral Hepat 2019; 26 Suppl 1:69-76. [PMID: 31380585 DOI: 10.1111/jvh.13154] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 05/15/2019] [Indexed: 12/15/2022]
Abstract
Achieving 'clinical cure' in children with chronic hepatitis B (CHB) with safe and effective antiviral treatment is an unmet medical need. Peginterferon (PegIFN) has higher hepatitis B s antigen (HBsAg) clearance than nucleoside analogs (NUC). Currently, studies on interferon (IFN) in the treatment of Chinese children with CHB are relatively rare. This study aimed to further explore the efficacy of PegIFNα-2a as an antiviral treatment in Chinese children and analyse the long-term follow-up after drug discontinuation. We enrolled 118 patients with CHB (2-16 years old, 79 cases are males) treated with PegIFNα-2a by the author in the Third People's Hospital of Kunming City from February 2009 to February 2015. The course of treatment was 52 weeks, with a follow-up period of 104 weeks. All the patients completed at least 1 dose, of which 104 completed at least 36 weeks of treatment and 104 weeks of follow-up. During treatment and follow-up, indicators such as alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA and HBV serological markers were monitored, and the efficacy and safety of PegIFNα-2a in the treatment of CHB patients were observed. Hepatitis B e antigen (HBeAg) clearance and seroconversion rates were 53.8% and 49%, respectively, when the drug was discontinued; 72.1% and 72.1%, respectively, at the end of the follow-up; and 98.2% and 98%, respectively, for sustained response. HBsAg clearance and seroconversion rates were 48.1% and 47.1%, respectively, when the drug was discontinued; 53.8% and 52.9%, respectively, at the end of the follow-up; and 94% and 95.9%, respectively, for sustained response. The HBV DNA suppression rate was 89.4% when the drug was discontinued, 90.4% at the end of the follow-up and 97.8% for sustained response. Two patients had virological relapse (2.3%) during follow-up; however, no clinical relapse occurred. Multivariate regression analysis showed that genotype B, weight < 25 kg or between 25 and 45 kg, and reduction of HBsAg by more than 1 log following 24 weeks of treatment were independent predictors of HBsAg clearance at the end of follow-up. Adverse events that occurred during treatment were similar to those reported in previous clinical studies on PegIFN. The results of this study showed that PegIFN was safe and effective in the treatment of children with CHB, and sustained response could be achieved after treatment. PegIFN treatment of children with CHB helps more achieve 'clinical cure'.
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Affiliation(s)
- Yunhua Liu
- Department of Hepatology, The Second People's Hospital of Yunnan Province, Kunming, China
| | - Hui Li
- Department of Hepatology, The Second People's Hospital of Yunnan Province, Kunming, China
| | - Xiaohui Yan
- Department of Hepatology, The Second People's Hospital of Yunnan Province, Kunming, China
| | - Jia Wei
- Department of Hepatology, The Second People's Hospital of Yunnan Province, Kunming, China
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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36
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Indolfi G, Easterbrook P, Dusheiko G, Siberry G, Chang MH, Thorne C, Bulterys M, Chan PL, El-Sayed MH, Giaquinto C, Jonas MM, Meyers T, Walsh N, Wirth S, Penazzato M. Hepatitis B virus infection in children and adolescents. Lancet Gastroenterol Hepatol 2019; 4:466-476. [PMID: 30982722 DOI: 10.1016/s2468-1253(19)30042-1] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease and associated morbidity and mortality worldwide. Vertical (mother-to-child) and horizontal early childhood transmission are the main routes of HBV transmission and are responsible for most chronic infections, including among adults who bear the greatest burden of morbidity and mortality. Universal hepatitis B immunisation at birth and in infancy is the key strategy for global elimination of HBV infection, and has been highly effective in reducing new vertical infections. However, global progress in scale-up of HBV testing and treatment has been slow in adults and children. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HBV infection in adolescents and children, and we highlight key differences from HBV infection in adults. The estimated global prevalence of HBV infection in children aged 5 years or younger is 1·3%. Most children are in the high-replication, low-inflammation phase of infection, with normal or only slightly raised aminotransferases; cirrhosis and hepatocellular carcinoma are rare. Although entecavir is approved and recommended for children aged 2-17 years, and tenofovir for those aged 12-18 years, a conservative approach to treatment initiation in children is recommended. Key actions to address current policy gaps include: validation of non-invasive tests for liver disease staging; additional immunopathogenesis studies in children with HBV infection; long-term follow-up of children on nucleoside or nucleotide analogue regimens to inform guidance on when to start treatment; evaluation of different treatment strategies for children with high rates of HBV replication; and establishment of paediatric treatment registries and international consortia to promote collaborative research.
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Affiliation(s)
- Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Florence, Italy
| | - Philippa Easterbrook
- Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland.
| | - Geoffrey Dusheiko
- King's College Hospital, London, UK; University College London Medical School, London, UK
| | - George Siberry
- Office of the US Global AIDS Coordinator, US Department of State, Washington, DC, USA
| | - Mei-Hwei Chang
- Department of Paediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Claire Thorne
- UCL Great Ormond Street Institute of Child Health, University College London, NIHR GOSH BRC, London, UK
| | - Marc Bulterys
- Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland
| | - Po-Lin Chan
- World Health Organization Regional Office for the Western Pacific, Manila, Philippines
| | - Manal H El-Sayed
- Department of Paediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Carlo Giaquinto
- Department of Women and Child Health, University of Padova, Padova, Italy
| | - Maureen M Jonas
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - Tammy Meyers
- Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, South Africa
| | - Nick Walsh
- Pan American Health Organization, World Health Organization Regional Office for the Americas, Washington, DC, USA
| | - Stefan Wirth
- Department of Paediatrics, Helios Medical Centre Wuppertal, Witten-Herdecke University, Witten, Germany
| | - Martina Penazzato
- Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland
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Hsu HY, Chang MH. Hepatitis B Virus Infection and the Progress toward its Elimination. J Pediatr 2019; 205:12-20. [PMID: 30244984 DOI: 10.1016/j.jpeds.2018.08.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/20/2018] [Accepted: 08/09/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Children's Hospital and College of Medicine, National Taiwan University, Taipei; Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Children's Hospital and College of Medicine, National Taiwan University, Taipei.
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Yang J, Yang G, He H, Ning L, Liu Z, Fu Q, Chen H, Deng H, Wang Z, Luo K. Association of characteristics of HBV quasispecies with hepatitis B surface antigen seroconversion after pegylated interferon-α-2a treatment in child patients. Antivir Ther 2018; 23:567-574. [PMID: 30095435 DOI: 10.3851/imp3262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND The correlation between hepatitis B surface antigen (HBsAg) seroconversion and the characteristics of HBV quasispecies (QS) before and during pegylated interferon-α-2a (PEG-IFN-α-2a) treatment in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) children has not yet been reported. METHODS 35 patients, including 18 HBsAg seroconverters (SS) and 17 non-seroconverters (SN), were enrolled. Serum samples were collected before treatment and at weeks 12 and 24 of treatment. Sequences within the basal core promoter/pre-core (BCP/PC) and S/reverse transcriptase (S/RT) region were analysed by next-generation sequencing. RESULTS There was no significant difference in the baseline diversity of HBV QS (Shannon entropy [Sn]; Hamming distance [HD]) in either region between the two groups. The baseline mutations A1762T/G1764A, C1913A, and T2003A/G or C2004T were correlated with non-response to therapy (P=0.025, P=0.036, P=0.032, respectively). After 24 weeks of therapy, HBV diversity within the BCP/PC region in the SS group notably declined (Sn: P=0.002; HD: P=0.011), while that of the SN group was nearly unchanged. As for the S/RT region, 24 weeks of treatment made no significant difference on QS diversity in either group. CONCLUSIONS Our data demonstrated that the baseline viral mutations and dynamic changes in HBV QS diversity within the BCP/PC region were closely related to HBsAg seroconversion in HBeAg-positive CHB children treated with PEG-IFN-α-2a.
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Affiliation(s)
- Juncheng Yang
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guifeng Yang
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haitang He
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lu Ning
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhihua Liu
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qunfang Fu
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Chen
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haohui Deng
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhanhui Wang
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kangxian Luo
- Department of Infectious Diseases and Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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