|
1
|
Cornberg M, Sandmann L, Jaroszewicz J, Kennedy P, Lampertico P, Lemoine M, Lens S, Testoni B, Lai-Hung Wong G, Russo FP. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2025:S0168-8278(25)00174-6. [PMID: 40348683 DOI: 10.1016/j.jhep.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.
Collapse
|
|
2
|
Shin H, Choi WM, Kim SU, Ko Y, Park Y, Park J, Hur MH, Park MK, Lee YB, Kim YJ, Yoon JH, Lee JH, Zoulim F. Lack of association between early on-treatment HBeAg seroclearance and development of hepatocellular carcinoma or decompensated cirrhosis. JHEP Rep 2024; 6:101089. [PMID: 38974365 PMCID: PMC11225842 DOI: 10.1016/j.jhepr.2024.101089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/26/2024] [Accepted: 04/02/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND & AIMS The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue (NA) treatment and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) remains unclear. Here, we aimed to investigate the association of HBeAg seroclearance during potent NA treatment with the development of HCC and decompensated cirrhosis. METHODS Using a multicenter historical cohort including 2,392 non-cirrhotic adult patients with HBeAg-positive CHB who initiated NA treatment with tenofovir or entecavir, the risk of HCC and decompensated cirrhosis was compared between patients who achieved HBeAg seroclearance within 36 months of NA treatment (the HBeAg-loss group) and those who did not (the HBeAg-maintained group), using inverse probability of treatment weighting. RESULTS Over a median of 6.6 years of NA treatment, 1,077 patients achieved HBeAg seroclearance (HBeAg loss rate = 6.0 per 100 person-years), 64 patients developed HCC (HCC incidence rate = 0.39 per 100 person-years), and 46 patients developed decompensated cirrhosis (decompensation incidence rate = 0.28 per 100 person-years). The HBeAg-loss and HBeAg-maintained groups had a similar risk of developing HCC (hazard ratio 0.89; 95% CI 0.47-1.68; p = 0.72) and decompensated cirrhosis (hazard ratio 0.98; 95% CI 0.48-1.81; p = 0.91). Compared with delayed HBeAg seroclearance beyond 10 years of NA treatment, the risk of HCC was comparable in those who achieved earlier HBeAg seroclearance at any time point within 10 years, regardless of baseline age and fibrotic burden. CONCLUSIONS Early HBeAg seroclearance during NA treatment was not associated with a reduced risk of development of HCC or decompensated cirrhosis in non-cirrhotic HBeAg-positive patients with CHB. IMPACT AND IMPLICATIONS The association between hepatitis B envelope antigen (HBeAg) seroclearance during long-term nucleos(t)ide analogue treatment and the risk of hepatocellular carcinoma in patients with chronic hepatitis B remains unclear. Our findings indicate that early on-treatment HBeAg seroclearance within 3 years was not associated with the development of hepatocellular carcinoma or decompensated cirrhosis. Achieving HBeAg seroclearance may not be an appropriate surrogate endpoint for preventing the development of liver-related outcomes in non-cirrhotic patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues.
Collapse
Affiliation(s)
- Hyunjae Shin
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Yunmi Ko
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Youngsu Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeayeon Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Moon Haeng Hur
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min Kyung Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| |
Collapse
|
|
3
|
Hao X, Fan R, Zeng HM, Hou JL. Hepatocellular Carcinoma Risk Scores from Modeling to Real Clinical Practice in Areas Highly Endemic for Hepatitis B Infection. J Clin Transl Hepatol 2023; 11:1508-1519. [PMID: 38161501 PMCID: PMC10752803 DOI: 10.14218/jcth.2023.00087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/04/2023] [Accepted: 06/02/2023] [Indexed: 01/03/2024] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and represents a global health challenge. Liver cancer ranks third in cancer-related mortality with 830,000 deaths and sixth in incidence with 906,000 new cases annually worldwide. HCC most commonly occurs in patients with underlying liver disease, especially chronic hepatitis B virus (HBV) infection in highly endemic areas. Predicting HCC risk based on scoring models for patients with chronic liver disease is a simple, effective strategy for identifying and stratifying patients to improve the early diagnosis rate and prognosis of HCC. We examined 23 HCC risk scores published worldwide in CHB patients with (n=10) or without (n=13) antiviral treatment. We also described the characteristics of the risk score's predictive performance and application status. In the future, higher predictive accuracy could be achieved by combining novel technologies and machine learning algorithms to develop and update HCC risk score models and integrated early warning and diagnosis systems for HCC in hospitals and communities.
Collapse
Affiliation(s)
- Xin Hao
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| | - Rong Fan
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| | - Hong-Mei Zeng
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin-Lin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Institute of Liver Diseases, Guangzhou, Guangdong, China
| |
Collapse
|
|
4
|
Tang L, Li Q, Chen L, Li X, Gu S, He W, Pan Q, Wang L, Sun J, Yi X, Li Y. IL-21 collaborates with anti-TIGIT to restore NK cell function in chronic HBV infection. J Med Virol 2023; 95:e29142. [PMID: 37815034 DOI: 10.1002/jmv.29142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/29/2023] [Accepted: 09/21/2023] [Indexed: 10/11/2023]
Abstract
Available therapies for chronic hepatitis B virus (HBV) infection are not satisfying, and interleukin-21 (IL-21) and checkpoint inhibitors are potential therapeutic options. However, the mechanism underlying IL-21 and checkpoint inhibitors in treating chronic HBV infection is unclear. To explore whether IL-21 and checkpoint inhibitors promote HBV clearance by modulating the function of natural killer (NK) cells, we measured the phenotypes and functions of NK cells in chronic HBV-infected patients and healthy controls on mRNA and protein levels. We found that chronic HBV infection disturbed the transcriptome of NK cells, including decreased expression of KLRK1, TIGIT, GZMA, PRF1, and increased expression of CD69. We also observed altered phenotypes and functions of NK cells in chronic HBV-infected patients, characterized by decreased NKG2D expression, increased TIGIT expression and impaired interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) production. Furthermore, these alterations cannot be restored by telbivudine treatment but can be partially restored by IL-21 and anti-TIGIT stimulation. IL-21 upregulated the expression of activating receptor CD16, CD69, and NKG2D on NK cells, enhanced IFN-γ production, cytolysis, and proliferation of NK cells, while anti-TIGIT promoted IFN-γ production in CD56dim subset exclusively in chronic HBV infected patients. Additionally, IL-21 was indispensable for anti-TIGIT in HBsAg clearance in mice bearing HBV. It enhanced IFN-γ production in splenic NK cells rather than intrahepatic NK cells, indicating a brand-new mechanism of IL-21 in HBV clearance when combined with anti-TIGIT. Overall, our findings contribute to the design of immunotherapy through enhancing the antiviral efficacy of NK cells in chronic HBV infection.
Collapse
Affiliation(s)
- Libo Tang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Quanrun Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Key Infectious Diseases Laboratory (Preparatory) of Yunnan Provincial Department of Education, Department of Infectious Diseases, School of Clinical Medicine, The First Affiliated Yunnan Provincial Clinical Medical Center (Branch) for Infectious Diseases, Hospital of Dali University, Dali University, Dali, Yunnan, China
| | - Liang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, China
| | - Xiaowei Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuqin Gu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiying He
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qingqing Pan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Liping Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianru Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Yi
- Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yongyin Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
5
|
Zhang Y, Gu Y, Yin S, Wang J, Zhang Z, Liu Y, Chen Y, Zhan J, Xue R, Yan X, Zhang S, Ding W, Chen Y, Li J, Huang R, Wu C. Baseline albumin-bilirubin score: a predictor for HBeAg clearance in patients with chronic hepatitis B after nucleos(t)ide analogue treatment. Eur J Gastroenterol Hepatol 2023; 35:1023-1029. [PMID: 37395182 DOI: 10.1097/meg.0000000000002598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
BACKGROUND Serum biomarkers for predicting HBeAg clearance in patients with chronic hepatitis B (CHB) virus infection during antiviral therapy remain lacking. This study aimed to investigate baseline albumin-bilirubin (ALBI) score for assessing HBeAg clearance in HBeAg-positive CHB patients treated with nucleos(t)ide analogues (NAs). METHODS Six hundred and ninety-nine HBeAg-positive CHB patients treated with first-line NAs were retrospectively included. Kaplan-Meier curves were used to compare the possibility of HBeAg clearance and HBeAg seroconversion in different ALBI groups. Cox regression models were used to identify factors associated with HBeAg clearance and HBeAg seroconversion. RESULTS Of the patients, 69.8% were male, with a median age of 36.0 years. 174 (24.9%) patients achieved HBeAg clearance after a median of 92.0 (interquartile range 48.0-134.0) weeks of antiviral treatment and 108 (15.5%) patients achieved HBeAg seroconversion. 74.0% and 26.0% of patients were classified as ALBI grade 1 and ALBI grade 2-3, respectively. ALBI grade 2-3 was identified as an independent predictor of HBeAg clearance (hazard ratio 1.570, 95% confidence interval 1.071-2.301, P = 0.021). The cumulative incidence of HBeAg clearance and HBeAg seroconversion was significantly higher in ALBI grade 2-3 group than group of ALBI grade 1 ( P < 0.001). Similar results were observed in different subgroups with different antiviral drugs, cirrhosis status, and ALT levels. CONCLUSION Baseline ALBI score may be a valuable indicator for predicting antiviral response in HBeAg-positive CHB patients treated with NAs.
Collapse
Affiliation(s)
- Yao Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
| | - Yan Gu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
- Institute of Viruses and Infectious Diseases, Nanjing University
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
- Institute of Viruses and Infectious Diseases, Nanjing University
| | - Zhiyi Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
| | - Yun Chen
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| | - Jie Zhan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| | - Ruifei Xue
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
| | - Shaoqiu Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
- Institute of Viruses and Infectious Diseases, Nanjing University
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
- Institute of Viruses and Infectious Diseases, Nanjing University
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
- Institute of Viruses and Infectious Diseases, Nanjing University
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing
| |
Collapse
|
|
6
|
Huang X, Yan M, Deng Z, Yao L, Han D, Sun L. Natural history of decompensated cirrhosis with serum hepatitis B DNA < 2000 IU/mL: a retrospective study. BMC Gastroenterol 2022; 22:452. [PMID: 36352372 PMCID: PMC9647958 DOI: 10.1186/s12876-022-02541-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022] Open
Abstract
Background and aims Patients with low HBV DNA levels (< 2000 IU/mL), HBV DNA negative, and HBsAg-negative hepatitis B virus(HBV)infection can still progress to decompensated cirrhosis; however, clinical research data in such patients, especially treatment-naïve patients, are currently insufficient. This study assessed the natural history of aforementioned patients. Methods We retrospectively reviewed the data of 250 patients with HBV-associated decompensated cirrhosis(HBV DNA < 2000 IU/mL) who had not been treated with antiviral medication. Results The mean age of the 250 patients was 53.90 ± 11.73 years and 183 patients (73.2%) were male. HBV DNA, HBsAg, and HBeAg positivity was detected in 77 (30.8%), 200 (80%), and 137 (54.8%) patients, respectively. HBsAg (odds ratio [OR], 3.303; 95% confidence interval [CI], 1.338–8.152; P = 0.010) and HBeAg (OR, 0.200; 95% CI, 0.107–0.376; P < 0.001) positivity were independent factors for low HBV DNA levels. The incidence of hepatocellular carcinoma (HCC) (P < 0.001) and portal vein thrombosis (P = 0.001) was higher in the low HBV DNA levels group. Multivariate analysis showed that HBV DNA positivity (OR, 3.548; 95% CI, 1.463–8.604; P = 0.005), HBeAg positivity (OR, 0.080; 95% CI, 0.022–0.289; P < 0.001), and glutamyltransferase (GGT) (OR, 1.003; 95% CI, 1.000–1.006; P = 0.040) were independent factors for HCC. Age was not related to the occurrence of cirrhosis complications. Conclusion Patients with decompensated cirrhosis with HBV DNA < 2000 IU/mL still had severe liver damage and could develop severe cirrhosis complications. HCC risk was higher in low HBV DNA levels patients. HBsAg positivity and HBeAg negativity may be associated to the occurrence of low HBV DNA levels.
Collapse
|
|
7
|
Xing L, Zeng R, Huang K, Xue J, Liu H, Zhao Z, Peng Y, Hu X, Liu C. Fuzheng Huayu Recipe and its active compounds inhibited HBeAg production by promoting TOMM34 gene expression in HBV-infected hepatocytes. Front Pharmacol 2022; 13:907921. [PMID: 36249820 PMCID: PMC9555080 DOI: 10.3389/fphar.2022.907921] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 09/06/2022] [Indexed: 11/23/2022] Open
Abstract
Background and aim: Fuzheng Huayu Recipe (FZHY) is a Chinese patent medicine (approval No. Z20020074) included in the national medical insurance catalogue, which is mainly used for anti-hepatic fibrosis treatment of hepatitis B virus (HBV) induced liver fibrosis and liver cirrhosis. In clinical practice, we discovered that FZHY might also have a direct anti-HBV effect on inhibiting HBeAg production, but the mechanism underlying was unclear. This study aimed to clarify the molecular mechanism of the inhibition effect of FZHY on HBeAg production. Methods: The decrease degree of serum HBeAg titer in FZHY + entecavir (ETV) group patients were analyzed through clinical data. C57BL/6N-Tg (1.28HBV)/Vst HBV transgenic mice were used for in vivo experiments. HepG2. 2.15 cells (wild-type HBV replication cells) were used for in vitro experiments. Results: The clinical study results showed that the decrease degree of serum HBeAg titer in FZHY+ETV group was significantly higher than that in ETV group after 48 weeks treatment. In vivo experiments results showed that FZHY could significantly reduce the serum HBeAg titer in HBV transgenic mice, and promote HBeAg seroconversion. In vitro experiments results showed that FZHY could reduce HBeAg titer dependently, but it did not significantly inhibit the expression of HBsAg and HBV-DNA. Further cell experiments in vitro discovered that TOMM34 might be the key target for FZHY to inhibit HBeAg production. The subsequent pharmacological screening experiment of 20 active compounds in FZHY showed that quercetin, baicalin and cordycepin could promote the expression of TOMM34 gene and reduce the production of HBeAg. Conclusion: In conclusion, FZHY and its active compounds quercetin, baicalin and cordycepin could inhibit HBeAg production by promoting the expression of TOMM34 gene in HBV-infected hepatocytes.
Collapse
Affiliation(s)
- Lu Xing
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rui Zeng
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Huang
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingbo Xue
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongliang Liu
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhimin Zhao
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuan Peng
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xudong Hu
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Xudong Hu, ; Chenghai Liu,
| | - Chenghai Liu
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- *Correspondence: Xudong Hu, ; Chenghai Liu,
| |
Collapse
|
|
8
|
Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
Collapse
Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| |
Collapse
|
|
9
|
Ma Z, Qin Y, Jia Y, Xie Y, Qi X, Guo Y, He J, Zhang Y, Li F, Yu J, Zhu H, Yang F, Zhang Y, Mao R, Zhang J. Thyroid dysfunction incidence and risk factors in Chinese chronic hepatitis B patients treated with pegylated interferon alpha: A long-term follow-up study. J Viral Hepat 2022; 29:412-419. [PMID: 35293082 DOI: 10.1111/jvh.13667] [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: 01/12/2022] [Accepted: 02/20/2022] [Indexed: 12/09/2022]
Abstract
The long-term impact, incidence and risk factors of thyroid dysfunction in chronic hepatitis B (CHB) patients receiving pegylated interferon (IFN) alpha (PegIFN-alpha) therapy remain unclear. We aim to investigate the long-term safety of thyroid dysfunction in CHB patients receiving PegIFN-alpha. A retrospective observational study of 425 CHB patients with normal baseline thyroid function was carried out. Patients were followed up over 10 years to assess thyroid function after receiving IFN. At the end of the IFN therapy, 67 patients (15.8%) had developed thyroid dysfunction, 31 patients (46.3%) had hyperthyroidism and 64.4% presented with subclinical thyroid dysfunction. In follow-up of thyroid dysfunction patients, 37 patients (74.0%) spontaneously regained normal thyroid function. Pretreatment thyroid-stimulating hormone (TSH) level, thyroid peroxidase antibody (TPOAb) positivity and free thyroxine (FT4) were independent risk factors associated with thyroid dysfunction incidence. High TSH level (OR = 9.866, 95%CI, 3.245-29.998) was associated with a greater likelihood of hypothyroidism. High FT4 levels (OR = 0.464, 95%CI, 0.248-0.868) indicate a low likelihood of thyroid dysfunction. Thyroid dysfunction is a common but acceptable side effect of IFN therapy for CHB. Most thyroid dysfunction is reversible. Pretreatment TSH level and TPOAb positivity are risk factors for thyroid dysfunction development during IFN therapy. A high TSH level predicts an increased incidence of hypothyroidism. Moreover, FT4 may be a protective factor for thyroid dysfunction.
Collapse
Affiliation(s)
- Zhenxuan Ma
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China.,Department of Geriatrics, National Clinical Research Center for Aging and Medicine, Huashan Hospital,Fudan University, Shanghai, China
| | - Yanli Qin
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Yidi Jia
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Yiran Xie
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Xun Qi
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Yifei Guo
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Jingjing He
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Yongmei Zhang
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Jie Yu
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Feifei Yang
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Yu Zhang
- Department of Geriatrics, National Clinical Research Center for Aging and Medicine, Huashan Hospital,Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases,Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital,Fudan University, Shanghai, China
| |
Collapse
|
|
10
|
Hepatocellular Carcinoma in Hepatitis B Virus-Infected Patients and the Role of Hepatitis B Surface Antigen (HBsAg). J Clin Med 2022; 11:jcm11041126. [PMID: 35207397 PMCID: PMC8878376 DOI: 10.3390/jcm11041126] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/09/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Hepatitis B virus (HBV) infection is among the main risk factors for HCC. The risk of HCC is not eliminated completely after viral suppression, due to HBV DNA integrated into human chromosomes. Cirrhosis, HBV viral DNA levels, age, male gender, the immune response of the host against HBV, and a combination of obesity and diabetes are among the main risk factors for HCC. Active viral replication and long-standing active disease with inflammation are associated with a higher risk of HCC. Treatment of HBV with nucleos(t)ide analogues (NAs) decreased HCC risk by effectively decreasing viral load and inflammation. Similar risk factors have been reported in hepatitis B patients after seroclearance. Studies have reported decreased risk of HCC after seroclearance, but there were also conflicting results from a few studies indicating no difference in risk of developing HCC. The difference in HCC rates could be because of other factors such as coinfection, occult HBV infection, family history, HBV genotype, and other comorbidities. Due to the persistent risk of HCC after seroclearance, HCC surveillance is critical for early detection, especially in high-risk patients. However, long-term studies might be needed to further validate the results.
Collapse
|
|
11
|
Li J, Chen H, Chen J, Zhou B, Hou J, Jiang DK. A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B. Pharmgenomics Pers Med 2021; 14:1505-1515. [PMID: 34848996 PMCID: PMC8627316 DOI: 10.2147/pgpm.s337962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/03/2021] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Granulysin (GNLY) is a cytotoxic granule that has been reported to have various antimicrobial activities. We evaluated the association between a missense variant in GNLY (rs11127) and treatment efficacy of pegylated interferon-alpha (PegIFNα) or nucleos(t)ide analogs (NUCs) in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS We included a total of 1823 patients with hepatitis B e antigen (HBeAg)-positive CHB (954 patients treated with PegIFNα and 869 patients treated with NUCs) in four Phase IV multicenter randomized controlled trials. The association of the GNLY rs11127 genotype with the combined response (CR), defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA level <2000 IU/mL was evaluated. A polygenic score (PGS) was constructed to evaluate the cumulative effect of multiple single-nucleotide polymorphisms (SNPs), including rs11127 and several other SNPs, STAT4 rs7574865, CFB rs12614, and CD55 rs28371597, which were reported to be associated with CR. RESULTS GNLY rs11127 was significantly associated with CR in patients treated with PegIFNα. The CR rate in patients with the rs11127 CC genotype was higher than that with the CT or TT genotype (40.98% vs 30.34% or 27.09%, P = 0.003). Furthermore, a PGS integrating GNLY rs11127 and three other SNPs was significantly associated with CR in PegIFNα-treated patients (P < 0.001). However, no significant correlation was found between GNLY rs11127 and CR in NUCs-treated patients. CONCLUSION GNLY rs11127 is an independent biomarker for predicting the response to PegIFNα therapy in HBeAg-positive CHB patients. Furthermore, the PGS, including GNLY rs11127, provides new insights for individualized treatment in clinical practice.
Collapse
Affiliation(s)
- Jing Li
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, People’s Republic of China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| |
Collapse
|
|
12
|
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.
Collapse
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
| |
Collapse
|
|
13
|
Liang KH, Chen SF, Lin YH, Chu YD, Lin YH, Lai MW, Lin CL, Yeh CT. Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9111539. [PMID: 34829768 PMCID: PMC8614833 DOI: 10.3390/biomedicines9111539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 01/04/2023] Open
Abstract
Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The N-Acetylgalactosaminyltransferase 14 (GALNT14) gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], p = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; p = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib.
Collapse
Affiliation(s)
- Kung-Hao Liang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: (K.-H.L.); (C.-T.Y.); Tel.: +886-2-28712121 (ext. 1296) (K.-H.L.); +886-3-3281200 (ext. 8129) (C.-T.Y.); Fax: 886-3-3282824 (C.-T.Y.)
| | - Sung-Fang Chen
- Department of Chemistry, National Taiwan Normal University, Taipei 106, Taiwan; (S.-F.C.); (Y.-H.L.)
| | - Yu-Hua Lin
- Department of Chemistry, National Taiwan Normal University, Taipei 106, Taiwan; (S.-F.C.); (Y.-H.L.)
| | - Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
- Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
- Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (K.-H.L.); (C.-T.Y.); Tel.: +886-2-28712121 (ext. 1296) (K.-H.L.); +886-3-3281200 (ext. 8129) (C.-T.Y.); Fax: 886-3-3282824 (C.-T.Y.)
| |
Collapse
|
|
14
|
Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
Collapse
Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
| |
Collapse
|
|
15
|
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
| | | |
Collapse
|
|
16
|
Liu Y, Veeraraghavan V, Pinkerton M, Fu J, Douglas MW, George J, Tu T. Viral Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Occurrence and Recurrence. Front Microbiol 2021; 12:665201. [PMID: 34194408 PMCID: PMC8236856 DOI: 10.3389/fmicb.2021.665201] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death. The most common risk factor for developing HCC is chronic infection with hepatitis B virus (HBV). Early stages of HBV-related HCC (HBV-HCC) are generally asymptomatic. Moreover, while serum alpha-fetoprotein (AFP) and abdominal ultrasound are widely used to screen for HCC, they have poor sensitivity. Thus, HBV-HCC is frequently diagnosed at an advanced stage, in which there are limited treatment options and high mortality rates. Serum biomarkers with high sensitivity and specificity are crucial for earlier diagnosis of HCC and improving survival rates. As viral-host interactions are key determinants of pathogenesis, viral biomarkers may add greater diagnostic power for HCC than host biomarkers alone. In this review, we summarize recent research on using virus-derived biomarkers for predicting HCC occurrence and recurrence; including circulating viral DNA, RNA transcripts, and viral proteins. Combining these viral biomarkers with AFP and abdominal ultrasound could improve sensitivity and specificity of early diagnosis, increasing the survival of patients with HBV-HCC. In the future, as the mechanisms that drive HBV-HCC to become clearer, new biomarkers may be identified which can further improve early diagnosis of HBV-HCC.
Collapse
Affiliation(s)
- Yuanyuan Liu
- Department of Infectious Diseases, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, China.,Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Vaishnavi Veeraraghavan
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,School of Medical Science, The University of Sydney, Camperdown, NSW, Australia
| | - Monica Pinkerton
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,School of Medical Science, The University of Sydney, Camperdown, NSW, Australia
| | - Jianjun Fu
- Department of Infectious Diseases, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia.,Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Thomas Tu
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
17
|
Jang TY, Wei YJ, Liu TW, Yeh ML, Liu SF, Hsu CT, Hsu PY, Lin YH, Liang PC, Hsieh MH, Ko YM, Tsai YS, Chen KY, Lin CC, Tsai PC, Wang SC, Huang CI, Lin ZY, Chen SC, Chuang WL, Huang JF, Dai CY, Huang CF, Yu ML. Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues. Sci Rep 2021; 11:8184. [PMID: 33854160 PMCID: PMC8047028 DOI: 10.1038/s41598-021-87679-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 03/30/2021] [Indexed: 12/20/2022] Open
Abstract
Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11-19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35-24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03-6.54, P < 0.001), male gender (HR/CI 2.69/1.29-5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03-1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04-19.09, P = 0.04) and BMI (HR/CI 1.11/1.03-1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.
Collapse
Affiliation(s)
- Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Department of Internal Medicine, Pingtung Hospital, Ministry of Health and Welfare, Ping-Tung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ju Wei
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Ta-Wei Liu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Fen Liu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Cheng-Ting Hsu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Po-Yao Hsu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Meng-Hsuan Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Yu-Min Ko
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Yi-Shan Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Kuan-Yu Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Ching-Chih Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
| | - Shu-Chi Wang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan.
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou Road, Kaohsiung, 807, Taiwan.
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
| |
Collapse
|
|
18
|
Chihab H, Badre W, Tahiri M, Jadid FZ, Zaidane I, Elfihry R, Marchio A, Pineau P, Ezzikouri S, Benjelloun S. IFNL4 rs12979860 polymorphism influences HBV DNA viral loads but not the outcome of HBV infection in Moroccan patients. Microbes Infect 2021; 23:104802. [PMID: 33607264 DOI: 10.1016/j.micinf.2021.104802] [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] [Received: 06/22/2020] [Revised: 01/20/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVES The interferon (IFN) is known to bridge innate and adaptive immune responses, and to play a critical role particularly against hepatitis B virus (HBV) infection. Defects in IFN signals may result, therefore, in attenuated responses against HBV. Accordingly, polymorphisms in genes coding for immune response effectors may affect the clinical outcome of HBV infection. We analyzed the putative association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection in Moroccan patients. METHODS In this study, 237 chronic HBV (CHB) patients and 129 spontaneously resolved HBV (SRB) individuals were enrolled and genotyped using a predesigned Taqman allelic discrimination assay. RESULTS Our data show a significant increase of HBV DNA loads in patients with IFNL4 rs12979860 CC genotype compared to patients with CT and TT genotypes (p = 0.0008). However, there was no consistent association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection. CONCLUSIONS Although IFNL4 rs12979860 polymorphism seems to modulate circulating HBV DNA levels, it is disconnected from chronic disease progression. This observation suggests that the role of rs12979860 in liver disease is restricted to viral control and inactive in the deleterious immune pathology that affects liver tissue. Taken together, our data suggest that rs12979860 CC genotypes could be useful as a predictor of success or failure of IFN-based therapy in chronic HBV-infected patients.
Collapse
Affiliation(s)
- Hajar Chihab
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Wafaa Badre
- Faculté de Médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Mohamed Tahiri
- Faculté de Médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Fatima-Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Raouia Elfihry
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Agnès Marchio
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.
| |
Collapse
|
|
19
|
Abstract
Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population starting from birth dose, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective, the cancer preventive efficacy support it as the first successful example of cancer preventive vaccine in human. Addition of hepatitis B immunoglobulin immediately after birth and antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are existing or possible emerging strategies to enhance the prevention efficacy of HBV infection and its related liver cancer. Secondary prevention with current antiviral agents may reduce the risk or delay the onset of HCC development, but could not eradicate HBV infection and HCC. Better antiviral therapeutic agents are needed for better secondary prevention.
Collapse
Affiliation(s)
- Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
20
|
Jeng WJ, Lok ASF. Is Cure of Hepatitis B Infection a Mission Possible? HEPATITIS B VIRUS AND LIVER DISEASE 2021:475-495. [DOI: 10.1007/978-981-16-3615-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
21
|
Chou R, Blazina I, Bougatsos C, Holmes R, Selph S, Grusing S, Jou J. Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2020; 324:2423-2436. [PMID: 33320229 DOI: 10.1001/jama.2020.19750] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Importance A 2014 review for the US Preventive Services Task Force (USPSTF) found antiviral therapy for hepatitis B virus (HBV) infection associated with improved intermediate outcomes, although evidence on clinical outcomes was limited. Objective To update the 2014 HBV screening review in nonpregnant adolescents and adults to inform the USPSTF. Data Sources Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (2014 to August 2019); with surveillance through July 24, 2020. Study Selection Randomized clinical trials (RCTs) on screening and antiviral therapy; cohort studies on screening, antiviral therapy clinical outcomes, and the association between achieving intermediate outcomes after antiviral therapy and clinical outcomes. Data Extraction and Synthesis One investigator abstracted data; a second investigator checked accuracy. Two investigators independently assessed study quality. Random-effects profile likelihood meta-analysis was performed. Results Thirty trials and 20 cohort studies, with a total of 94 168 participants, were included. No study directly evaluated the effects of screening for HBV infection vs no screening on clinical outcomes such as mortality, hepatocellular carcinoma, or cirrhosis. Screening strategies that focused on risk factors such as ever having immigrated from high-prevalence countries and demographic and behavioral risk factors would identify nearly all HBV infection cases. In 1 study (n = 21 008), only screening immigrants from high-prevalence countries would miss approximately two-thirds of infected persons. Based on 18 trials (n = 2972), antiviral therapy compared with placebo or no treatment was associated with greater likelihood of achieving intermediate outcomes, such as virologic suppression and hepatitis B e-antigen (HBeAg) or hepatitis B surface antigen loss or seroconversion; the numbers needed to treat ranged from 2.6 for virologic suppression to 17 for HBeAg seroconversion. Based on 12 trials (n = 4127), first-line antiviral therapies were at least as likely as nonpreferred therapies to achieve intermediate outcomes. Based on 16 trials (n = 4809), antiviral therapy might be associated with improved clinical outcomes, but data were sparse and imprecise. Nine cohort studies (n = 3893) indicated an association between achieving an intermediate outcome following antiviral therapy and improved clinical outcomes but were heterogeneous (hazard ratios ranged from 0.07 to 0.87). Antiviral therapy was associated with higher risk of withdrawal due to adverse events vs placebo or no antiviral therapy. Conclusions and Relevance There was no direct evidence for the clinical benefits and harms of HBV screening vs no screening. Antiviral therapy for HBV infection was associated with improved intermediate outcomes and may improve clinical outcomes.
Collapse
Affiliation(s)
- Roger Chou
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
- Division of General Internal Medicine and Geriatrics; Oregon Health & Science University, Portland
| | - Ian Blazina
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Christina Bougatsos
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Rebecca Holmes
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Shelley Selph
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
- Department of Family Medicine, Oregon Health & Science University, Portland
| | - Sara Grusing
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Janice Jou
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
- Division of Gastroenterology and Hepatology; Oregon Health & Science University, Portland
| |
Collapse
|
|
22
|
Li S, Saviano A, Erstad DJ, Hoshida Y, Fuchs BC, Baumert T, Tanabe KK. Risk Factors, Pathogenesis, and Strategies for Hepatocellular Carcinoma Prevention: Emphasis on Secondary Prevention and Its Translational Challenges. J Clin Med 2020; 9:E3817. [PMID: 33255794 PMCID: PMC7760293 DOI: 10.3390/jcm9123817] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/11/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.
Collapse
Affiliation(s)
- Shen Li
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Antonio Saviano
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Derek J. Erstad
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Yujin Hoshida
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Department of Internal Medicine, Dallas, TX 75390, USA;
| | - Bryan C. Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| | - Thomas Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France;
| | - Kenneth K. Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA; (S.L.); (D.J.E.); (B.C.F.)
| |
Collapse
|
|
23
|
Li X, Zhou D, Chi X, Li Q, Wang L, Lu B, Mao D, Wu Q, Wang X, Zhang M, Xue J, Li Y, Lu W, Guo J, Jiang F, Zhang X, Li Z, Yang X, Guo H, Gan D, He L, Luo L, Zhang L, Du H, Ye Y. Entecavir combining Chinese herbal medicine for HBeAg-positive chronic hepatitis B patients: a randomized, controlled trial. Hepatol Int 2020; 14:985-996. [PMID: 33128206 DOI: 10.1007/s12072-020-10097-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/30/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Traditional Chinese medicine (TCM) is widely accepted and prescribed in China alongside Nucleoside analogs (NAs). In this double-blind, placebo-controlled, randomized, multi-center trial, we evaluated whether entecavir (ETV) plus TCM formulas Tiao-Gan-Yi-Pi granule (TGYP) and Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) increase the rate of hepatitis B e antigen (HBeAg) loss in Chinese patients. METHODS 596 eligible participants were randomly assigned, in a 1:1 ratio, to two study groups in this 108-week trial: The experiment group was assigned ETV plus the TCM formula. The control group was assigned ETV plus a TCM placebo. We compared the rate of HBeAg loss by the end of week 108 between the two arms as the primary outcome. Secondary outcomes included hepatitis B surface antigen (HBsAg) level, proportion of undetectable HBV-DNA, and liver enzymes (ALT, AST, GGT) at week 108. RESULTS The combination therapy achieved superior HBeAg loss at 108 weeks, without additional adverse events. The rate of HBeAg loss at week 108 was 37.54% (95% CI 31.9-43.2%) in the experiment group and 27.21% (95% CI 22.0-32.4%) in the control group. There was a statistically significant difference between the two arms of 10.33% (95% CI 8.4-12.3%, p = 0.008). The DNA loss rate, serum HBsAg level, and liver enzymes were similar between the groups by the end of 108th week. CONCLUSION Combining the Chinese herbal formula with ETV therapy demonstrated superior HBeAg clearance compared with ETV monotherapy. This finding indicates that this combined therapy could produce an improved therapeutic effect and safety profile. CLINICAL TRIAL NUMBER ChiCTR-TRC-12002784 (Chinese Clinical Trial Registry).
Collapse
Affiliation(s)
- Xiaoke Li
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Daqiao Zhou
- Department of Hepatology, Shenzhen TCM Hospital, No. 1 Fuhua Road, Futian District, Shenzhen, 518033, China
| | - Xiaoling Chi
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Dade Road 111, Guangzhou, 510120, Guangdong, China
| | - Qin Li
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312 Xihong road, Gulou District, Fujian, 350025, Fuzhou, China
| | - Li Wang
- Department of Hepatology, Public Health Clinical Center of Chengdu, No. 377 Jingming Road, Jinjiang District, Chengdu, 610066, Sichuan, China
| | - Bingjiu Lu
- Department of Hepatology, Liaoning Hospital of TCM, Huanggu District, No. 33, Beiling Street, Shenyang, 110032, Liaoning, China
| | - Dewen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9, Dongge road, Nanning, 530023, Guangxi, China
| | - Qikai Wu
- Department of Hepatology, The Third People's Hospital of Shenzhen, No. 29 Bujibulan Road, Longgang District, Shenzhen, 518112, China
| | - Xianbo Wang
- Department of Hepatology, Beijing Ditan Hospital, No. 8 Jingshun East Road, Chaoyang District, Beijing, 100015, China
| | - Mingxiang Zhang
- Department of Hepatology, The Sixth People's Hospital of Shenyang, No. 85 Heping south road, Heping District, Shenyang, 110006, Liaoning, China
| | - Jingdong Xue
- Department of Hepatology, Shaanxi Hospital of TCM, No. 4 Xihuamen, Lianhu District, Xi'an, 710003, Shaanxi, China
| | - Yong Li
- Department of Hepatology, The Affiliated Hospital of Shandong University of TCM, No. 42 Wenhua West Road, Jinan, 250011, Shandong, China
| | - Wei Lu
- Department of Hepatology, Tianjin Second People's Hospital, No.7 Sudi South Road, Nankai District, Tianjin, 300192, China
| | - Jianchun Guo
- Department of Hepatology, Xixi Hospital of Hangzhou, No. 2 Hengbu road, Liuxiazhen, Xihu District, Hangzhou, 310023, Zhejiang, China
| | - Feng Jiang
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Xinwei Zhang
- Department of Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, No.100 West Fourth Ring Road, Beijing, 100039, China
| | - Zhiguo Li
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Xianzhao Yang
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Hui Guo
- Department of Hepatology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 314 An Shan Xi Road, Nan Kai District, Tianjin, 300193, China
| | - Danan Gan
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Liyun He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medicine Sciences, No. 16, Dongzhimen South Street, Dongcheng District, Beijing, 100700, China
| | - Lin Luo
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medicine Sciences, No. 16, Dongzhimen South Street, Dongcheng District, Beijing, 100700, China
| | - Ludan Zhang
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Hongbo Du
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China.
| | - Yong'an Ye
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China.
| |
Collapse
|
|
24
|
Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
Collapse
|
|
25
|
Lenci I, Milana M, Grassi G, Manzia TM, Gazia C, Tisone G, Angelico R, Baiocchi L. Hepatitis B virus recurrence after liver transplantation: An old tale or a clear and present danger? World J Gastroenterol 2020; 26:2166-2176. [PMID: 32476783 PMCID: PMC7235198 DOI: 10.3748/wjg.v26.i18.2166] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/12/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) recurrence after liver transplantation (LT) has been described more than 50 years ago. Similarly, to other clinical conditions, in which impairment of host immune defense favors viral replication, early reports described in details recurrence and reactivation of HBV in liver transplant recipients. The evidence of a possible, severe, clinical evolution of HBV reappearance in a significant percentage of these patients, allowed to consider, for some years, HBV positivity a contraindication for LT. Moving from the old to the new millennium this picture has changed dramatically. Several studies contributed to establish efficient prophylactic protocols for HBV recurrence and with the advent of more potent anti-viral drugs an increased control of infection was achieved in transplanted patients as well as in the general immune-competent HBV population. Success obtained in the last decade led some authors to the conclusion that HBV is now to consider just as a "mere nuisance". However, with regard to HBV and LT, outstanding issues are still on the table: (1) A standard HBV prophylaxis protocol after transplant has not yet been clearly defined; (2) The evidence of HBV resistant strains to the most potent antiviral agents is claiming for a new generation of drugs; and (3) The possibility of prophylaxis withdrawal in some patients has been demonstrated, but reliable methods for their selection are still lacking. The evolution of LT for HBV is examined in detail in this review together with the description of the strategies adopted to prevent HBV recurrence and their pros and cons.
Collapse
Affiliation(s)
- Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Giuseppe Grassi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Tommaso M Manzia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Carlo Gazia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Giuseppe Tisone
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Roberta Angelico
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| |
Collapse
|
|
26
|
Wu S, Luo W, Wu Y, Chen H, Peng J. HBsAg quantification predicts off-treatment response to interferon in chronic hepatitis B patients: a retrospective study of 250 cases. BMC Gastroenterol 2020; 20:121. [PMID: 32316928 PMCID: PMC7171920 DOI: 10.1186/s12876-020-01263-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 04/05/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND For chronic hepatitis B (CHB) patients without willingness to extend the routine duration of interferon (IFN) therapy, it is important to identify patients who will benefit from treatment cessation. Hepatitis B surface antigen (HBsAg) quantification is recommended for management of IFN therapy. At present, the understanding on end-of-treatment (EOT) HBsAg level predicting post-treatment response to IFN is still finite. METHODS A total of 2451 non-cirrhosis, HBsAg-postive patients treated with IFN-based therapy during the period from December 2010 to December 2017 at Nanfang Hospital were enrolled in this study. Serum HBsAg levels at EOT were measured to evaluate the associations between EOT HBsAg levels (Group 1, HBsAg > 0.05 and ≤ 10 IU/mL; Group 2, HBsAg > 10 and ≤ 200 IU/mL; Group 3, HBsAg > 200 IU/mL) with post-treatment HBsAg loss. Chi-squared, t-test,,Kaplan-Meier analysis, Cox regression analysis, and Multivariate Logistic regression analysis were used to analyse and evaluate differences between the there groups. RESULTS The cumulative HBsAg loss rates 5 years after treatment in Group 1-3 were 30.4% (17/56), 9.8%(4/41) and 0%(0/153) (p < 0.001). An EOT HBsAg level of > 10 IU/mL showed relatively high negative predictive value (NPV) of up to 97.9% for HBsAg loss. Low baseline HBsAg level < 25,000 IU/mL, on-treatment HBsAg decline > 1 log10IU/mL at week 24 and EOT HBsAg level ≤ 10 IU/mL were found significantly associated with HBsAg loss. A total of 6 patients have achieved HBsAg loss at EOT and 17 patients with EOT HBsAg level ≤ 10 IU/mL have achieved post-treatment HBsAg loss. Baseline characteristics, dynamic changes of on-treatment HBsAg and duration of IFN therapy were balanced across patients with EOT or post-treatment HBsAg loss. CONCLUSION EOT HBsAg level can serve as a monitoring indicator for IFN therapy. EOT HBsAg level ≤ 10 IU/mL was found to lead to high rate of post-treatment HBsAg loss. For patients without willingness to extend IFN treatment, off-treatment follow-up could be considered when HBsAg level decreased to ≤10 IU/mL.
Collapse
Affiliation(s)
- Shuai Wu
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Wenfan Luo
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Yin Wu
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Hongjie Chen
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| |
Collapse
|
|
27
|
Li XK, Zhang MX, Shao FZ, Zhou DQ, Xue JD, Liu TJ, Chi XL, Lu BJ, Wang XB, Li Q, Li J, Mao DW, Yang HS, Yang HZ, Zhao WX, Li Y, Zhang GL, Zhao YM, Zou JD, Liu MY, Zhang KK, Yang XZ, Gan DN, Li Y, Zhang P, Li ZG, Li S, Ye YA. Adefovir Dipivoxil plus Chinese Medicine in HBeAg-Positive Chronic Hepatitis B Patients: A Randomized Controlled 48-Week Trial. Chin J Integr Med 2020; 26:330-338. [PMID: 31919749 DOI: 10.1007/s11655-020-3250-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients. METHODS A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented. RESULTS The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns. CONCLUSION Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).
Collapse
Affiliation(s)
- Xiao-Ke Li
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ming-Xiang Zhang
- Department of Hepatology, the Sixth People's Hospital of Shenyang, Shenyang, 110006, China
| | - Feng-Zhen Shao
- Department of Hepatology, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, China
| | - Da-Qiao Zhou
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
| | - Jing-Dong Xue
- Department of Hepatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, 710003, China
| | - Tie-Jun Liu
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Xiao-Ling Chi
- Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Bing-Jiu Lu
- Department of Hepatology, Liaoning Hospital of Traditional Chinese Medicine, Shenyang, 110032, China
| | - Xian-Bo Wang
- Department of Hepatology, Beijing Ditan Hospital, Beijing, 100015, China
| | - Qin Li
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
| | - Jun Li
- Department of Hepatology, the 302 Military Hospital of PLA, Beijing, 100039, China
| | - De-Wen Mao
- Department of Hepatology, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530023, China
| | - Hua-Sheng Yang
- Department of Integrated Traditional Chinese Medicine and Western Medicine, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Hong-Zhi Yang
- Department of Traditional Chinese Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Wen-Xia Zhao
- Department of Gastroenterology, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, China
| | - Yong Li
- Department of Hepatology, Shandong Hospital of Traditional Chinese Medicine, Jinan, 250011, China
| | - Guo-Liang Zhang
- Department of Gastroenterology, Anhui Hospital of Traditional Chinese Medicine, Hefei, 230031, China
| | - Yi-Ming Zhao
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, China
| | - Jian-Dong Zou
- Clinical Research Center, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, 210029, China
| | - Meng-Yang Liu
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ke-Ke Zhang
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xian-Zhao Yang
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Da-Nan Gan
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ying Li
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Peng Zhang
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhi-Guo Li
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Shuo Li
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yong-An Ye
- Department of Gastroenterology, Institute of Liver Disease, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
| |
Collapse
|
|
28
|
Chen H, Sun J, Zhou B, Xie Q, Liang X, Fan R, Conran C, Xu J, Ji Y, Zhang X, Sun L, Jia J, Wang G, Hou J, Jiang DK. Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha. Clin Gastroenterol Hepatol 2020; 18:196-204.e8. [PMID: 31042581 DOI: 10.1016/j.cgh.2019.04.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/16/2019] [Accepted: 04/19/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. METHODS We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. RESULTS We found a significant association between rs7574865 genotype and CR (P = .004) and loss of HBsAg (P = .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P = .811) or loss of HBsAg (P=.439). CONCLUSIONS In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.
Collapse
Affiliation(s)
- Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Qing Xie
- Department of Infectious Diseases, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xier Liang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Carly Conran
- University of Illinois College of Medicine, Chicago, Illinois
| | - Jianfeng Xu
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - Yuan Ji
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois
| | - Xinxin Zhang
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Sun
- Xiamen Amoytop Biotech Co Ltd, Xiamen, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guiqiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China; Peking University International Hospital, Beijing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.
| |
Collapse
|
|
29
|
Chen Y, Li JJ, Chen R, Li G, Ji J. Dynamics of HBV surface antigen related end points in chronic hepatitis B infection: a systematic review and meta-analysis. Antivir Ther 2020; 25:203-215. [PMID: 32609658 DOI: 10.3851/imp3366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND In chronic hepatitis B (CHB) treatment, hepatitis B surface antigen (HBsAg) is regarded as a promising clinical end point associated with long-term clinical outcomes. We performed a meta-analysis to characterize the dynamics and influencing factors of HBsAg. METHODS Literature search was conducted through PubMed from January 1995 to May 2015 for papers reporting HBsAg in patients receiving various antiviral treatments. We conducted weighted linear regression to select for potential influencing factors on maximum HBsAg loss percentage, and subgroup analysis to calculate the pooled estimates of maximum HBsAg loss and seroconversion percentage following treatment of interferon (IFN), nucleoside analogue (NUC) or combination therapies (NUC+IFN), respectively. Study heterogeneity was assessed through sensitivity test and I-square statistics. RESULTS We collected data from 24 papers involving 6,674 adult CHB patients. In most studies, average HBsAg level decreased during treatment but relapsed after treatment cessation, while HBsAg loss or seroconversion percentage continued to increase or remained stable after treatment cessation. No strong relationship was observed between maximum HBsAg change and its baseline level. The pooled estimates of maximum HBsAg loss percentage for IFN (5.3%, 2.7-7.9%) and NUC+IFN (5.2%, 3.1-7.4%) were significantly higher than that of NUC (0.93%, 0.29-1.6%). Higher maximum HBsAg loss percentage is associated with longer peak time. Pooled maximum HBsAg seroconversion percentage estimates were 1.6%, 0.56% and 6.2% for IFN, NUC and NUC+IFN. CONCLUSIONS With respect to HBsAg lowering, this meta-analysis confirmed the importance of longer treatment duration and addition of IFN, which revealed the potential value of immune-based therapies.
Collapse
Affiliation(s)
- Yusi Chen
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.,Present address: Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | | | - Rong Chen
- School of Pharmaceutical Sciences, Peking University, Beijing, China.,Present address: Center for Drug Evaluation, National Medical Products Administration, Beijing, China
| | - Gailing Li
- Clinical Pharmacology and Pharmacometrics, Janssen China R&D, Beijing, China
| | - Jia Ji
- Clinical Pharmacology and Pharmacometrics, Janssen China R&D, Beijing, China
| |
Collapse
|
|
30
|
Li H, Yan L, Shi Y, Lv D, Shang J, Bai L, Tang H. Hepatitis B Virus Infection: Overview. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:1-16. [PMID: 31741331 DOI: 10.1007/978-981-13-9151-4_1] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatitis B virus (HBV) is a DNA virus, belonging to the Hepadnaviridae family. It is a partially double-stranded DNA virus with a small viral genome (3.2 kb). Chronic HBV infection remains a global public health problem. If left untreated, chronic HBV infection can progress to end-stage liver disease, such as liver cirrhosis and hepatocellular carcinoma (HCC). In recent years, tremendous advances in the field of HBV basic and clinical research have been achieved, ranging from the HBV biological characteristics, immunopathogenesis, and animal models to the development of new therapeutic strategies and new drugs against HBV. In this overview, we begin with a brief history of HBV discovery and treatment milestones. We then briefly summarize the HBV research advances, which will be detailed in the following chapters.
Collapse
Affiliation(s)
- Hong Li
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Libo Yan
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ying Shi
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Duoduo Lv
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jin Shang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lang Bai
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Tang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| |
Collapse
|
|
31
|
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.
Collapse
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
| |
Collapse
|
|
32
|
Yuwaki K, Shimazu T, Yamagiwa Y, Inoue M, Goto A, Yamaji T, Iwasaki M, Sawada N, Tsugane S. Association between serum liver enzymes and all-cause mortality: The Japan Public Health Center-based Prospective Study. Liver Int 2019; 39:1566-1576. [PMID: 30566759 DOI: 10.1111/liv.14030] [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: 09/05/2018] [Revised: 11/28/2018] [Accepted: 12/11/2018] [Indexed: 01/23/2023]
Abstract
BACKGROUND & AIMS The association of serum liver enzyme levels with all-cause mortality in individuals without hepatitis B virus or hepatitis C virus infection is inconsistent. We aimed to investigate all-cause and non-liver disease mortality according to levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) stratified by hepatitis virus infection status in a Japanese cohort. METHODS Participants were 7243 men and 13 513 women aged 40-69 years at the baseline survey in 1993-1994. Multivariate-adjusted hazard ratios of death from the baseline health check-up to December 2012 were calculated with a Cox proportional hazards model controlling for potential confounding factors. RESULTS During follow-up, 2235 deaths in men and 1901 deaths in women were identified. All serum liver enzymes were associated with all-cause mortality in each sex and hepatitis virus infection status. In participants without infection, those with more than twice the upper level of normal (ULN), which was defined as 30 IU/L for AST and ALT and 50 IU/L for GGT, had a higher risk of non-liver disease mortality compared to those below the ULN (HR 1.69; 95% confidence interval 1.13-2.53, 1.49; 1.02-2.18, 1.39; 1.11-1.73, 1.72; 1.08-2.74 and 1.72; 1.10-2.69 for AST, ALT, and GGT in men and AST and GGT in women, respectively), except for ALT in women. CONCLUSIONS In participants without hepatitis virus infection, serum liver enzyme levels were positively associated with all-cause mortality. Similar associations were also found for non-liver disease mortality.
Collapse
Affiliation(s)
- Keiichi Yuwaki
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.,Underwriting and Medical Department, The Dai-ichi Life Insurance Company, Limited, Tokyo, Japan
| | - Taichi Shimazu
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Yoko Yamagiwa
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Manami Inoue
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Atsushi Goto
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Taiki Yamaji
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Motoki Iwasaki
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Norie Sawada
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | | |
Collapse
|
|
33
|
Wu YL, Shen CL, Chen XY. Antiviral treatment for chronic hepatitis B: Safety, effectiveness, and prognosis. World J Clin Cases 2019; 7:1784-1794. [PMID: 31417924 PMCID: PMC6692272 DOI: 10.12998/wjcc.v7.i14.1784] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/02/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
The goal of chronic hepatitis B (CHB) therapy is to improve the patient prognosis through the sustained inhibition of viral replication. However, due to the uncertainty and potentially unlimited duration of the treatment course, nucleus(t)ide analogue (NA) resistance and safety, financial costs and patient compliance, different endpoints of antiviral treatment have been proposed in CHB prevention and treatment guidelines. Different treatment endpoints are closely associated with the safety of drug withdrawal and improvements in prognosis. Antiviral treatment suppresses HBV DNA replication, drug withdrawal leads to relapse, and long-term treatment causes drug safety and resistance issues. Although hepatitis B e antigen seroconversion based on HBV DNA inhibition is considered as “a satisfactory endpoint”, drug withdrawal still leads to high relapse rates. Hepatitis B surface antigen (HBsAg) clearance is the “ideal endpoint” in terms of the safety of drug withdrawal and improvements in prognosis. However, the HBsAg clearance rate is low using the conventional single drug treatment and fixed course regimens. Recently, the application of an “optimized antiviral treatment strategy” has improved the HBsAg clearance rate, and make an “ideal endpoint” possible. This article reviews the different antiviral treatment endpoints in terms of the safety of drug withdrawal, improvements in prognosis and relevant advances.
Collapse
Affiliation(s)
- Ya-Li Wu
- International Medical Department, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Cheng-Li Shen
- Division of Surgical Oncology, James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Xin-Yue Chen
- International Medical Department, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| |
Collapse
|
|
34
|
Yan Z, Wu D, Hu H, Zeng J, Yu X, Xu Z, Zhou Z, Zhou X, Yang G, Young JA, Gao L. Direct Inhibition of Hepatitis B e Antigen by Core Protein Allosteric Modulator. Hepatology 2019; 70:11-24. [PMID: 30664279 PMCID: PMC6618080 DOI: 10.1002/hep.30514] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 01/10/2019] [Indexed: 12/24/2022]
Abstract
Hepatitis B e antigen (HBeAg) is an important immunomodulator for promoting host immune tolerance during chronic hepatitis B (CHB) infection. In patients with CHB, HBeAg loss and seroconversion represent partial immune control of CHB infection and are regarded as valuable endpoints. However, the current approved treatments have only a limited efficacy in achieving HBeAg seroconversion in HBeAg-positive patients. Hepatitis B virus (HBV) core protein has been recognized as an attractive antiviral target, and two classes of core protein allosteric modulator (CpAM) have been discovered: the phenylpropenamides (PPAs) and the heteroaryldihydropyrimidines (HAPs). However, their differentiation and potential therapeutic benefit beyond HBV DNA inhibition remain to be seen. Here, we show that in contrast to PPA series compound AT-130, a HAP CpAM, HAP_R01, reduced HBeAg levels in multiple in vitro and in vivo HBV experimental models. Mechanistically, we found that HAP_R01 treatment caused the misassembly of capsids formed by purified HBeAg in vitro. In addition, HAP_R01 directly reduces HBeAg levels by inducing intracellular precore protein misassembly and aggregation. Using a HAP_R01-resistant mutant, we found that HAP_R01-mediated HBeAg and core protein reductions were mediated through the same mechanism. Furthermore, HAP_R01 treatment substantially reduced serum HBeAg levels in an HBV mouse model. Conclusion: Unlike PPA series compound AT-130, HAP_R01 not only inhibits HBV DNA levels but also directly reduces HBeAg through induction of its misassembly. HAP_R01, as well as other similar CpAMs, has the potential to achieve higher anti-HBeAg seroconversion rates than currently approved therapies for patients with CHB. Our findings also provide guidance for dose selection when designing clinical trials with molecules from HAP series.
Collapse
Affiliation(s)
- Zhipeng Yan
- Roche Innovation Center ShanghaiShanghaiChina
| | - Daitze Wu
- Roche Innovation Center ShanghaiShanghaiChina
| | - Hui Hu
- Roche Innovation Center ShanghaiShanghaiChina
| | - Jing Zeng
- Roche Innovation Center ShanghaiShanghaiChina
| | - Xin Yu
- Roche Innovation Center ShanghaiShanghaiChina
| | - Zhiheng Xu
- Roche Innovation Center ShanghaiShanghaiChina
| | - Zheng Zhou
- Roche Innovation Center ShanghaiShanghaiChina
| | - Xue Zhou
- Roche Innovation Center ShanghaiShanghaiChina
| | - Guang Yang
- Roche Innovation Center ShanghaiShanghaiChina
| | | | - Lu Gao
- Roche Innovation Center ShanghaiShanghaiChina
| |
Collapse
|
|
35
|
Chen J, Hu Y, Chen L, Liu W, Mu Y, Liu P. The effect and mechanisms of Fuzheng Huayu formula against chronic liver diseases. Biomed Pharmacother 2019; 114:108846. [PMID: 30965233 DOI: 10.1016/j.biopha.2019.108846] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/18/2019] [Accepted: 04/01/2019] [Indexed: 12/12/2022] Open
Abstract
Fuzheng Huayu formula (FZHY) is a traditional Chinese medicine formula composed of Radix Salvia Miltiorrhizae, Cordyceps, Semen Persicae, Gynostemma Pentaphyllammak, Pollen Pini, Fructus Schisandrae Chinensis that is used to treat chronic liver diseases in China. We here describe the pharmacological actions of FZHY in this review. We also describe and provide updates on recent advances in the medical applications and the basic research of mechanisms of FZHY formula. FZHY has been shown to have no serious adverse reactions and exerts antifibrotic effects through targeting more than one molecule.
Collapse
Affiliation(s)
- Jiamei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yonghong Hu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Long Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yongping Mu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai, 201203, China; E-Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
36
|
Paccoud O, Surgers L, Lacombe K. [Hepatitis B virus infection: Natural history, clinical manifestations and therapeutic approach]. Rev Med Interne 2019; 40:590-598. [PMID: 30982550 DOI: 10.1016/j.revmed.2019.03.333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/16/2019] [Accepted: 03/23/2019] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis B infection remains a major public-health problem, with approximately 260 million world-wide cases of infection. Recent advances in the understanding of the natural history of chronic hepatitis B infection have led to progress in the care of infected patients. Sustained viral suppression is now possible for a majority of treated patients and is associated with a decrease in the morbidity and mortality attributable to cirrhosis and hepatocellular carcinoma. Complete cure is however not yet possible, due to the long-term persistence of viral DNA in hepatocytes of treated patients. Assessing the risk of viral reactivation in patients receiving immunosuppressive therapy is an increasingly frequent situation in clinical practice and its management is guided by both the patient's serological status and the potency of the immunosuppressive regimen. This review aims to present the clinical and biological presentations of chronic hepatitis B infection, the modalities of antiviral treatment, and how to assess the risk of viral reactivation in patients receiving immunosuppressive therapy.
Collapse
Affiliation(s)
- O Paccoud
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France
| | - L Surgers
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France; Sorbonne université, CIMI équipe 13, Inserm U1135, 75005 Paris, France
| | - K Lacombe
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France; Sorbonne université, Inserm UMR-S1136, IPLESP, 75005 Paris, France.
| |
Collapse
|
|
37
|
Tarao K, Nozaki A, Ikeda T, Sato A, Komatsu H, Komatsu T, Taguri M, Tanaka K. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment. Cancer Med 2019; 8:1054-1065. [PMID: 30791221 PMCID: PMC6434205 DOI: 10.1002/cam4.1998] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/27/2018] [Accepted: 01/06/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. METHODS The PubMed database was examined (1989-2017) for studies published in English language regarding the prospective follow-up results for the development of HCC in various liver diseases. A meta-analysis was performed for each liver disease. RESULTS The annual incidence (%) of HCC in the non-cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non-cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73-fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07-fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88-fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79-fold), and (e) NASH (0.03%→1.35%, 45.00-fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow-up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. CONCLUSIONS When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.
Collapse
Affiliation(s)
- Kazuo Tarao
- Tarao’s Gastroenterological ClinicYokohamaJapan
| | - Akito Nozaki
- Gastroenterological Center, Medical CenterYokohama City UniversityYokohamaJapan
| | - Takaaki Ikeda
- Gastroenterology DepartmentYokosuka General Hospital UwamachiYokosukaJapan
| | - Akira Sato
- Division of Gastroenterology, Department of Internal MedicineSt. Marianna University, Yokohama City Seibu HospitalYokohamaJapan
| | - Hirokazu Komatsu
- Department of GastroenterologyYokohama Municipal Citizen’s HospitalYokohamaJapan
| | - Tatsuji Komatsu
- Department Clinical ResearchNational Hospital Organization, Yokohama Medical CenterYokohamaJapan
| | - Masataka Taguri
- Department of Data ScienceYokohama City UniversityYokohamaJapan
| | | |
Collapse
|
|
38
|
Zhou K, Contag C, Whitaker E, Terrault N. Spontaneous loss of surface antigen among adults living with chronic hepatitis B virus infection: a systematic review and pooled meta-analyses. Lancet Gastroenterol Hepatol 2019; 4:227-238. [PMID: 30679109 DOI: 10.1016/s2468-1253(18)30308-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 09/14/2018] [Accepted: 09/17/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Spontaneous loss of HBsAg (known as functional cure) in patients with chronic hepatitis B virus (HBV) infection significantly reduces liver-related complications. HBsAg loss has been suggested to be higher in non-endemic regions than in endemic regions in individual studies. We systematically determined a pooled annual rate of HBsAg loss in adults with untreated chronic HBV infection and examined the effect of regional endemicity. METHODS In this systematic review and meta-analysis, we searched PubMed and Embase for observational cohort studies and non-treatment arms of randomised controlled trials reporting proportions of patients with chronic HBV infection that achieved spontaneous HBsAg loss, published up to Oct 1, 2018. We excluded randomised controlled trials from meta-analyses because of substantial cohort differences. Two reviewers (KZ and CC) independently extracted data from accepted full-text studies, with discrepancies discussed with a third reviewer (NT). We assessed rate of HBsAg loss, and stratified results by whether the underlying cohort arose primarily from an endemic region (defined as having prevalence of chronic HBV greater than 2%) or non-endemic region. This study is registered with PROSPERO, number CRD42018074086. FINDINGS Of 5186 studies screened, 67 (11 randomised controlled trials, 39 prospective and 17 retrospective cohort studies) met the inclusion criteria and 56 were included in meta-analyses after exclusion of randomised controlled trials. Spontaneous HBsAg loss occurred in 3837 (7·8%) of 48 972 patients, with cumulative 352 381 person-years of follow-up. The pooled annual incidence of HBsAg loss was 1·17% (95% CI 0·94-1·41, I2=97%). Rates did not differ by endemicity: 1·19% (0·88-1·54) in endemic versus 1·29% (0·99-1·62) in non-endemic cohorts. INTERPRETATION Globally, spontaneous HBsAg loss occurs infrequently (about 1% per year) in treatment-naive adults with chronic HBV infection. The low and homogeneous rate of HBsAg loss highlights the need for new therapeutics aimed at achieving functional cure across different patient groups and geographical regions. FUNDING NIH National Institute of Diabetes and Digestive and Kidney Diseases.
Collapse
Affiliation(s)
- Kali Zhou
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Caitlin Contag
- Department of Medicine, Stanford University, Palo Alto, CA, USA
| | - Evans Whitaker
- Department of Library Science, University of California San Francisco, San Francisco, CA, USA
| | - Norah Terrault
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
| |
Collapse
|
|
39
|
O'Brien TR, Yang HI, Groover S, Jeng WJ. Genetic Factors That Affect Spontaneous Clearance of Hepatitis C or B Virus, Response to Treatment, and Disease Progression. Gastroenterology 2019; 156:400-417. [PMID: 30287169 DOI: 10.1053/j.gastro.2018.09.052] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment.
Collapse
Affiliation(s)
- Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sarah Groover
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| |
Collapse
|
|
40
|
Coffin CS, Fung SK, Alvarez F, Cooper CL, Doucette KE, Fournier C, Kelly E, Ko HH, Ma MM, Martin SR, Osiowy C, Ramji A, Tam E, Villeneuve JP. Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada. CANADIAN LIVER JOURNAL 2018; 1:156-217. [PMID: 35992619 PMCID: PMC9202759 DOI: 10.3138/canlivj.2018-0008] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 08/01/2023]
Abstract
Hepatitis B virus (HBV) infection is an important public health problem in Canada. In keeping with evolving evidence and understanding of HBV pathogenesis, the Canadian Association for the Study of Liver Disease periodically publishes HBV management guidelines. The goals of the 2018 guidelines are to (1) highlight the public health impact of HBV infection in Canada and the need to improve diagnosis and linkage to care, (2) recommend current best-practice guidelines for treatment of HBV, (3) summarize the key HBV laboratory diagnostic tests, and (4) review evidence on HBV management in special patient populations and include more detail on management of HBV in pediatric populations. An overview of novel HBV tests and therapies for HBV in development is provided to highlight the recent advances in HBV clinical research. The aim and scope of these guidelines are to serve as an up-to-date, comprehensive resource for Canadian health care providers in the management of HBV infection.
Collapse
Affiliation(s)
- Carla S. Coffin
- Cumming School of Medicine, University of Calgary, Calgary, Alberta
| | - Scott K. Fung
- Faculty of Medicine, University of Toronto, Toronto, Ontario
| | - Fernando Alvarez
- Centre hospitalier de l’université de Montréal (CHUM)—CHU Sainte-Justine, Montreal, Québec
| | - Curtis L. Cooper
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario
| | - Karen E. Doucette
- Division of Infectious Diseases, University of Alberta, Edmonton, Alberta
| | - Claire Fournier
- Department of Medicine, Université de Montréal, Montreal, Québec
| | - Erin Kelly
- Division of Gastroenterology, Department of Medicine, University of Ottawa, Ottawa, Ontario
| | - Hin Hin Ko
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia
| | - Mang M Ma
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta
| | | | - Carla Osiowy
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba
| | - Alnoor Ramji
- St. Paul’s Hospital, Vancouver, British Columbia
| | - Edward Tam
- LAIR Centre, Vancouver, British Columbia
| | | |
Collapse
|
|
41
|
Yu JH, Jin YJ, Lee JW, Lee DH. Remaining hepatocellular carcinoma risk in chronic hepatitis B patients receiving entecavir/tenofovir in South Korea. Hepatol Res 2018; 48:862-871. [PMID: 29761604 DOI: 10.1111/hepr.13194] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/16/2018] [Accepted: 05/04/2018] [Indexed: 02/08/2023]
Abstract
AIM We aimed to identify the incidence rate of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with entecavir or tenofovir in South Korea, and to identify predictors of HCC development in these patients. METHODS Between January 2007 and December 2015, 582 CHB patients initially received entecavir (n = 406, 69.8%) or tenofovir (n = 176, 30.2%) for CHB. RESULTS During a median follow-up of 57.1 months, HCC developed in 38 (6.5%) of the 582 patients, regardless of antiviral agent type. Entecavir- and tenofovir-treated patients had similar HCC development rates (P = 0.471). For the 582 patients, 2-, 4-, and 6-year cumulative HCC development rates were 2.6%, 4.4%, and 8.3%, respectively, and the 2-, 4-, and 6-year cumulative HCC development rates of patients with liver cirrhosis were significantly greater than those of patients without liver cirrhosis (6.2%, 9.8%, and 18.4% vs. 0.3%, 1.1%, and 2.2%, respectively; P < 0.001). Older (≥60 years) patients, regardless of the presence of cirrhosis, and cirrhotic patients aged ≥40 years showed significantly higher risk of HCC development compared to others (both P < 0.05). Multivariate analysis showed that an older age (≥50 years; hazard ratio [HR] 5.02, P = 0.009), and the presence of cirrhosis (HR 4.95, P = 0.002) independently predicted HCC development. CONCLUSIONS The 6-year cumulative HCC development rate was 6.5% in CHB patients treated with entecavir or tenofovir. Age ≥50 years and liver cirrhosis were found to predict HCC development in these patients.
Collapse
Affiliation(s)
- Jung Hwan Yu
- Digestive Disease Center, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Young-Joo Jin
- Digestive Disease Center, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Jin-Woo Lee
- Digestive Disease Center, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea
| | - Don-Haeng Lee
- Digestive Disease Center, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, South Korea.,The National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders (NCEED), Incheon, South Korea.,Utah-Inha Drug Delivery Systes and Advanced Therapeutics Research Center, Incheon, South Korea
| |
Collapse
|
|
42
|
Zhou TC, Lai X, Feng MH, Tang Y, Zhang L, Wei J. Systematic review and meta-analysis: Development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis e antigen seroconversion. J Viral Hepat 2018; 25:1172-1179. [PMID: 29741285 DOI: 10.1111/jvh.12928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/10/2018] [Indexed: 12/27/2022]
Abstract
Hepatitis B e antigen (HBeAg) seroconversion is considered to have significantly favourable clinical outcomes for patients with chronic hepatitis B (CHB). However, inconsistent study results suggest that hepatocellular carcinoma (HCC) still occurs in patients with HBeAg seroconversion. We performed a systematic review and meta-analysis to determine the incidence of HCC in patients with CHB after HBeAg seroconversion. Web of Science, PubMed and Embase databases were searched through January 2017. The incidence of HCC in CHB patients after HBeAg seroconversion was pooled using a random-effects model or fix-effects model. Sixteen studies were finally included, involving 4910 patients with HBeAg seroconversion. The overall pooled proportion suggested that 3.33% (95% confidence interval (CI): 2.28%-4.58%) of patients with CHB develop HCC despite HBeAg seroconversion. In patients with HBeAg seroconversion without cirrhosis, the pooled proportion of HCC development was 0.94% (95% CI: 0.15%-2.4%). Moreover, patients with cirrhosis, active hepatitis, or aged greater than 40 years at the time of HBeAg seroconversion were at significantly higher risk for HCC development. HBeAg seroconversion was significantly associated with a reduced risk of HCC compared with persistently positive HBeAg (RR = 0.58, 95% CI: 0.35-0.97, P = .04). Despite the reduced risk with HBeAg seroconversion, HCC can still occur in a proportion of patients with CHB after HBeAg seroconversion. Long-term monitoring is needed for patients with established cirrhosis, active hepatitis or those older than 40 years at the time of HBeAg seroconversion.
Collapse
Affiliation(s)
- T-C Zhou
- Central Lab, Liver Disease Research Center, the Second People's Hospital of Yunnan Province (The Fourth Affiliated Hospital of Kunming Medical University), Kunming, China
| | - X Lai
- Central Lab, Liver Disease Research Center, the Second People's Hospital of Yunnan Province (The Fourth Affiliated Hospital of Kunming Medical University), Kunming, China
| | - M-H Feng
- Central Lab, Liver Disease Research Center, the Second People's Hospital of Yunnan Province (The Fourth Affiliated Hospital of Kunming Medical University), Kunming, China
| | - Y Tang
- The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - L Zhang
- Central Lab, Liver Disease Research Center, the Second People's Hospital of Yunnan Province (The Fourth Affiliated Hospital of Kunming Medical University), Kunming, China
| | - J Wei
- Central Lab, Liver Disease Research Center, the Second People's Hospital of Yunnan Province (The Fourth Affiliated Hospital of Kunming Medical University), Kunming, China
| |
Collapse
|
|
43
|
Ren P, Cao Z, Mo R, Liu Y, Chen L, Li Z, Zhou T, Lu J, Liu Y, Guo Q, Chen R, Zhou H, Xiang X, Cai W, Wang H, Bao S, Xu Y, Gui H, Xie Q. Interferon-based treatment is superior to nucleos(t)ide analog in reducing HBV-related hepatocellular carcinoma for chronic hepatitis B patients at high risk. Expert Opin Biol Ther 2018; 18:1085-1094. [PMID: 30182763 DOI: 10.1080/14712598.2018.1518423] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND The effect of nucleos(t)ide analogs (NAs) versus interferon (IFN) on the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is controversial. We assessed whether antiviral strategy affected HCC development in CHB patients at different HCC risks. METHODS 1112 CHB patients with antiviral therapy were included in this retrospective study. Patients treated with NAs only were classified into NAs group (n = 682) while those received IFN treatment with or without NAs were defined as IFN group (n = 430). Propensity score matching (PSM) was applied to minimize baseline differences. RESULTS Totally, 31 patients developed HCC during follow-up (median 5.41 years). The cumulative HCC incidence at 10 years was significantly lower in the IFN group than NAs group (2.7% vs 8.0%, p < 0.001). Similar results were obtained in the PSM-cohort. Patients with IFN-based treatment were less likely to develop HCC than those with NAs (Hazard ratio = 0.15; 95% CI 0.04-0.66; p = 0.012). Subgroup analyses demonstrated that this superiority of IFN in reducing HCC development was obvious in patients at high- but not low-risk of HCC. CONCLUSIONS Reduction of HCC development was more significant in CHB patients at higher HCC risk with IFN-based therapy than NAs treatment.
Collapse
Affiliation(s)
- Peipei Ren
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Zhujun Cao
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Ruidong Mo
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Yuhan Liu
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Lichang Chen
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Ziqiang Li
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Tianhui Zhou
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Jie Lu
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Yunye Liu
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Qing Guo
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Rong Chen
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Huijuan Zhou
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Xiaogang Xiang
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Wei Cai
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Hui Wang
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Shisan Bao
- b Discipline of Pathology , the University of Sydney , Sydney , NSW , Australia
| | - Yumin Xu
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Honglian Gui
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Qing Xie
- a Department of Infectious Diseases , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| |
Collapse
|
|
44
|
Ye YA, Li XK, Zhou DQ, Chi XL, Li Q, Wang L, Lu BJ, Mao DW, Wu QK, Wang XB, Zhang MX, Xue JD, Li Y, Lu W, Guo JC, Jiang F, Zhang XW, Du HB, Yang XZ, Guo H, Gan DN, Li ZG. Chinese Herbal Medicine Combined with Entecavir for HBeAg Positive Chronic Hepatitis B: Study Protocol for a Multi-Center, Double-Blind Randomized-Controlled Trial. Chin J Integr Med 2018; 24:653-660. [PMID: 30209792 DOI: 10.1007/s11655-018-3011-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The domestic prevalence of chronic hepatitis B (CHB) in China is 7.18% in 2006, imposing great societal healthcare burdens. Nucleot(s)ide analogues (NUCs) anti-hepatitis B virus (HBV) therapies are widely applied despite the relatively low rate of seroconversion and high risk of drug-resistant mutation. More effective treatments for CHB deserve further explorations. Combined therapy of NUCs plus Chinese herbal medicine (CHM) is widely accepted in China, which is recognized as a prospective alternative approach. The study was primarily designed to confirm the hypothesis that Tiaogan-Yipi Granule (, TGYP) or Tiaogan-Jianpi-Jiedu Granule (, TGJPJD) plus entecavir tablet (ETV) was superior over ETV monotherapy in enhancing HBeAg loss rate. METHODS The study was a nationwide, large-scale, multi-center, double-blind, randomized, placebo-controlled trial with a designed duration of 108 weeks. A total of 16 hospitals and 596 eligible Chinese HBeAg positive CHB patients were enrolled from November 2012 to September 2013 and randomly allocated into 2 groups in 1:1 ratio via central randomization system: experimental group (EG) and control group (CG). Subjects in EG received CM formulae (TGYP or TGJPJD, 50 g per dose, twice daily) plus ETV tablet (or ETV placebo) 0.5 mg per day in the first 24 weeks (stage 1), and CHM granule plus ETV tablet (0.5 mg per day) from week 25 to 108 (stage 2). Subjects in CG received CHM Granule placebo plus ETV tablet (0.5 mg per day) for 108 weeks throughout the trial. The assessments of primary outcomes (HBV serum markers and HBV-DNA) were conducted by a third-party College of American Pathologists (CAP) qualified laboratory. Adverse effects were observed in the hospitals of recruitment. DISCUSSION The study was designed to compare the curative effect of CM plus ETV and ETV monotherapy in respect of HBeAg loss, which is recognized by the European Association for the Study of the Liver as "a valuable endpoint". We believe this trial could provide a reliable status for patients' "journey" towards durable responses after treatment discontinuation. The trial was registered before recruitment on Chinese Clinical trial registry (No. ChiCTR-TRC-12002784, Version 1.0, 2015/12/23).
Collapse
Affiliation(s)
- Yong-An Ye
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Xiao-Ke Li
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Da-Qiao Zhou
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, 518033, China
| | - Xiao-Ling Chi
- Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Qin Li
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
| | - Li Wang
- Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, 610066, China
| | - Bing-Jiu Lu
- Department of Hepatology, Liaoning Hospital of Traditional Chinese Medicine, Shenyang, 110032, China
| | - De-Wen Mao
- Department of Hepatology, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530023, China
| | - Qi-Kai Wu
- Department of Hepatology, the Third People's Hospital of Shenzhen, Shenzhen, Guangdong Province, 518112, China
| | - Xian-Bo Wang
- Department of Hepatology, Beijing Ditan Hospital, Beijing, 100015, China
| | - Ming-Xiang Zhang
- Department of Hepatology, the Sixth People's Hospital of Shenyang, Shenyang, 110006, China
| | - Jing-Dong Xue
- Department of Hepatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, 710003, China
| | - Yong Li
- Department of Hepatology, Shandong Hospital of Traditional Chinese Medicine, Jinan, 250011, China
| | - Wei Lu
- Department of Hepatology, the Second People's Hospital of Tianjin, Tianjin, 300000, China
| | - Jian-Chun Guo
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, 310023, China
| | - Feng Jiang
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xin-Wei Zhang
- Department of Hepatology, 302 Military Hospital of China, Beijing, 100039, China
| | - Hong-Bo Du
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xian-Zhao Yang
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Hui Guo
- Department of Hepatology, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, China
| | - Da-Nan Gan
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhi-Guo Li
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| |
Collapse
|
|
45
|
Mani SKK, Andrisani O. Interferon signaling during Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma. Cytokine 2018; 124:154518. [PMID: 30126685 DOI: 10.1016/j.cyto.2018.08.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/09/2018] [Accepted: 08/11/2018] [Indexed: 02/06/2023]
Abstract
Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. The World Health Organization estimates that globally 257 million people are chronic HBV carriers at risk of developing liver cancer. Current therapies for prevention and treatment of HCC are inadequate. Although interferon-based treatment strategies hold great promise for combating chronic infection and HCC, many patients do not respond to the IFN-based drugs for reasons not completely understood. Interferon signaling plays key roles in activation of innate and adaptive immunity. However, HBV has evolved various mechanisms to suppress IFN signaling. In this review, we present the basics about HBV infection and interferon signaling. Next, we discuss mechanisms through which HBV downregulates the function -activity and transcription- of the transcription factor STAT1 during acute and chronic infection. STAT1 is activated in response to all types (I/II/III) of interferon signaling and is essential in mediating all types (I/II/III) of interferon responses. Lastly, we discuss emerging evidence from different human cancers linking loss of interferon signaling to aggressive cancer and cancer stem cells. Whether the same occurs during HBV-associated hepatocarcinogenesis is discussed and currently under investigation.
Collapse
Affiliation(s)
- Saravana Kumar Kailasam Mani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
| | - Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
| |
Collapse
|
|
46
|
Abstract
An estimated 240 million people worldwide are chronically infected with the hepatitis B virus (HBV). Despite readily available vaccination, HBV infections remain highly prevalent. As established HBV infections constitute a strong risk factor for developing hepatocellular carcinoma their treatment is a major task for the health system. Unfortunately, HBV is not curable with today's medicine. Approximately 15 million HBV patients have developed a hepatitis delta (HDV) infection on top of their HBV infection. The patients superinfected with this satellite virus suffer from a more severe disease development. The knowledge of the viruses, their classifications, clinical implications, treatment options and efforts to increase the drug variety are compiled in this review. The current standard therapies include nucleosidic reverse transcriptase inhibitors and interferon. As the known treatments fail to cure HBV and HDV, targeted treatment is highly warranted. The focus of this review is set on the drugs currently under clinical investigation. Furthermore, strategies for the development of targeted treatment, and compounds with novel mode of action are described.
Collapse
|
|
47
|
Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article. Middle East J Dig Dis 2018; 10:133-148. [PMID: 30186577 PMCID: PMC6119836 DOI: 10.15171/mejdd.2018.103] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
Currently, liver fibrosis and its complications are regarded as critical health problems.
With the studies showing the reversible nature of liver fibrogenesis, scientists have focused
on understanding the underlying mechanism of this condition in order to develop new
therapeutic strategies. Although hepatic stellate cells are known as the primary cells
responsible for liver fibrogenesis, studies have shown contributing roles for other cells,
pathways, and molecules in the development of fibrosis depending on the etiology of
liver fibrosis. Hence, interventions could be directed in the proper way for each type of
liver diseases to better address this complication. There are two main approaches in clinical
reversion of liver fibrosis; eliminating the underlying insult and targeting the fibrosis
process, which have variable clinical importance in the treatment of this disease. In this
review, we present recent concepts in molecular pathways of liver fibrosis reversibility
and their clinical implications.
Collapse
Affiliation(s)
- Hedyeh Ebrahimi
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Naderian
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- Associate Professor, The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
48
|
Abstract
IMPORTANCE More than 240 million individuals worldwide are infected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who are untreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer. OBSERVATIONS Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovir disoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation and fibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk of hepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss with undetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and 1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48 weeks and is not associated with the development of resistance; however, its use is limited by poor tolerability and adverse effects such as bone marrow suppression and exacerbation of existing neuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, and tenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance compared with older agents (lamivudine and adefovir) and should be considered as the first-line treatment. CONCLUSIONS AND RELEVANCE Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates are low, most patients will require therapy indefinitely.
Collapse
Affiliation(s)
- Lydia S Y Tang
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| | - Emily Covert
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| | - Eleanor Wilson
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore
| |
Collapse
|
|
49
|
Zu J, Li M, Zhuang G, Liang P, Cui F, Wang F, Zheng H, Liang X. Estimating the impact of test-and-treat strategies on hepatitis B virus infection in China by using an age-structured mathematical model. Medicine (Baltimore) 2018; 97:e0484. [PMID: 29668627 PMCID: PMC5916706 DOI: 10.1097/md.0000000000010484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The potential impact of increasing test-and-treat coverage on hepatitis B virus (HBV) infection remains unclear in China. The objective of this study was to develop a dynamic compartmental model at a population level to estimate the long-term effect of this strategy.Based on the natural history of HBV infection and 3 serosurvey data of hepatitis B in China, we proposed an age- and time-dependent discrete model to predict the number of new HBV infection, the number of chronic HBV infection, and the number of HBV-related deaths for the time from 2018 to 2050 under 5 different test-and-treat coverage and compared them with current intervention policy.Compared with current policy, if the test-and-treat coverage was increased to 100% since 2018, the numbers of chronic HBV infection, new HBV infection, and HBV-related deaths in 2035 would be reduced by 26.60%, 24.88%, 26.55%, respectively, and in 2050 it would be reduced by 44.93%, 43.29%, 43.67%, respectively. In contrast, if the test-and-treat coverage was increased by 10% every year since 2018, then the numbers of chronic HBV infection, new HBV infection, and HBV-related deaths in 2035 would be reduced by 21.81%, 20.10%, 21.40%, respectively, and in 2050 it would be reduced by 41.53%, 39.89%, 40.32%, respectively. In particular, if the test-and-treat coverage was increased to 75% since 2018, then the annual number of HBV-related deaths would begin to decrease from 2018. If the test-and-treat coverage was increased to above 25% since 2018, then the hepatitis B surface antigen (HBsAg) prevalence for population aged 1 to 59 years in China would be reduced to below 2% in 2035. Our model also showed that in 2035, the numbers of chronic HBV infection and HBV-related deaths in 65 to 69 age group would be reduced the most (about 1.6 million and 13 thousand, respectively).Increasing test-and-treat coverage would significantly reduce HBV infection in China, especially in the middle-aged people and older people. The earlier the treatment and the longer the time, the more significant the reduction. Implementation of test-and-treat strategy is highly effective in controlling hepatitis B in China.
Collapse
Affiliation(s)
- Jian Zu
- School of Mathematics and Statistics
| | | | - Guihua Zhuang
- School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi
| | - Peifeng Liang
- Department of Statistics, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia
| | - Fuqiang Cui
- Health Science Center, Peking University, Beijing
| | - Fuzhen Wang
- Chinese Center for Disease Control and Prevention, Beijing, P. R. China
| | - Hui Zheng
- Chinese Center for Disease Control and Prevention, Beijing, P. R. China
| | - Xiaofeng Liang
- Chinese Center for Disease Control and Prevention, Beijing, P. R. China
| |
Collapse
|
|
50
|
Lasfar A, de laTorre A, Abushahba W, Cohen-Solal KA, Castaneda I, Yuan Y, Reuhl K, Zloza A, Raveche E, Laskin DL, Kotenko SV. Concerted action of IFN-α and IFN-λ induces local NK cell immunity and halts cancer growth. Oncotarget 2018; 7:49259-49267. [PMID: 27363032 PMCID: PMC5226505 DOI: 10.18632/oncotarget.10272] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 05/16/2016] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. No significant improvement has been reported with currently available systemic therapies. IFN-α has been tested in both clinic and animal models and only moderate benefits have been observed. In animal models, similar modest antitumor efficacy has also been reported for IFN-λ, a new type of IFN that acts through its own receptor complex. In the present study, the antitumor efficacy of the combination of IFN-α and IFN-λ was tested in the BNL mouse hepatoma model. This study was accomplished by using either engineered tumor cells (IFN-α/IFN-λ gene therapy) or by directly injecting tumor-bearing mice with IFN-α/IFN-λ. Both approaches demonstrated that IFN-α/IFN-λ combination therapy was more efficacious than IFN monotherapy based on either IFN-α or IFN-λ. In complement to tumor surgery, IFN-α/IFN-λ combination induced complete tumor remission. Highest antitumor efficacy has been obtained following local administration of IFN-α/IFN-λ combination at the tumor site that was associated with strong NK cells tumor infiltration. This supports the use of IFN-α/IFN-λ combination as a new cancer immunotherapy for stimulating antitumor response after cancer surgery.
Collapse
Affiliation(s)
- Ahmed Lasfar
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Andrew de laTorre
- Department of Surgery, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.,St Joseph's Medical Center, Paterson, NJ, USA
| | - Walid Abushahba
- Department of Microbiology, Biochemistry and Molecular Genetics, Center for Immunity and Inflammation, University Hospital Cancer Center, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, NJ, USA
| | - Karine A Cohen-Solal
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.,Section of Surgical Oncology Research, Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Ismael Castaneda
- Department of Surgery, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Yao Yuan
- Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Kenneth Reuhl
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Andrew Zloza
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.,Section of Surgical Oncology Research, Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Elizabeth Raveche
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.,Department of Pathology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Sergei V Kotenko
- Department of Microbiology, Biochemistry and Molecular Genetics, Center for Immunity and Inflammation, University Hospital Cancer Center, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, NJ, USA
| |
Collapse
|