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Chang LJ, Hao CQ, Rao GR, Xu LL, Li J, Cheng Y, Zheng LJ, Wu CW, Chen HX, Chen ZR, Lian JQ, Wu SH, Luo LM, Zhang WL, Zhang Y. Recurrence risk factors for chronic hepatitis B virus-infected patients who achieve functional cure with pegylated interferon-α-2b-based therapy: a multicenter pilot study. Virol J 2025; 22:146. [PMID: 40390028 PMCID: PMC12087174 DOI: 10.1186/s12985-025-02761-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 04/25/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Hepatitis B surface antigen (HBsAg) clearance is an achievable treatment endpoint for chronic hepatitis B virus (HBV)-infected patients. Pegylated interferon-α (PEG-IFN-α) induces higher rate of HBsAg clearance than nucleos(t)ide analogues. However, the influencing factors associated with HBsAg recurrence have not been fully elucidated. The aim of this study was to evaluate the risk factors for recurrence in chronic HBV-infected patients who achieved functional cure with PEG-IFN-α-2b-based treatment. METHODS A multicenter retrospective study was conducted. All patients received PEG-IFN-α-2b-based therapy, achieved HBV DNA negativity and HBsAg clearance, and were followed-up for at least 48 weeks after discontinuation of medications. The demographic data, as well as virological, serological, and biochemical indicators, were collected at baseline, therapy cessation, and during followed-up. Logistic regression analysis was subsequently performed. RESULTS A total of 101 chronic HBV-infected patients who achieved HBsAg loss with PEG-IFN-α-2b-based therapy were enrolled. The median treatment time was 24.00 (14.50, 37.50) weeks, and the median consolidation time was 11.00 (0.00, 24.00) weeks. HBsAg recurrence was found in 16 patients after a median 70.00 (48.00, 96.00) week follow-up, with a cumulative recurrence rate of 15.84%. A higher platelet count was associated with a slightly increased HBsAg recurrence risk at therapy cessation, whereas a shorter consolidation time was associated with an elevated HBsAg recurrence risk during followed-up. The appearance of anti-HBs presented a robustly reduced HBsAg recurrence risk at both therapy cessation and followed-up. No HBV DNA positivity or occurrence of end-stage liver disease was observed during treatment or followed-up. CONCLUSION The cumulative HBsAg recurrence rate was 15.84% after discontinuation of medications in chronic HBV-infected patients who achieved functional cure with PEG-IFN-α-2b-based therapy. The presence of anti-HBs reduced the HBsAg recurrence risk. CLINICAL TRIAL REGISTRATION This trial is a part of ZhuFeng Project (ClinicalTrials.gov, identifier NCT04035837) and a part of E-Cure Study (ClinicalTrials.gov, identifier NCT05182463).
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Affiliation(s)
- Li-Jun Chang
- Department of Infectious Diseases, Yuncheng Central Hospital Affiliated to Shanxi Medical University, 3690 Hedong East Rd, Yuncheng, Shanxi Province, 044000, China
| | - Chun-Qiu Hao
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd, Baqiao District, Xi'an, Shaanxi Province, 710038, China
| | - Gui-Rong Rao
- Department of Central Laboratory, Air Force Hospital of Southern Theatre Command, Guangzhou, Guangdong Province, 510602, China
| | - Lin-Li Xu
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 17 Changle West Rd, Xi'an, Shaanxi Province, 710032, China
| | - Jing Li
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd, Baqiao District, Xi'an, Shaanxi Province, 710038, China
| | - Yan Cheng
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd, Baqiao District, Xi'an, Shaanxi Province, 710038, China
| | - Li-Jun Zheng
- Department of Infectious Diseases, Yuncheng Central Hospital Affiliated to Shanxi Medical University, 3690 Hedong East Rd, Yuncheng, Shanxi Province, 044000, China
| | - Cun-Wen Wu
- Department of Infectious Diseases, Air Force Hospital of Southern Theatre Command, 801 Dongfeng East Rd, Guangzhou, Guangdong Province, 510602, China
| | - Han-Xian Chen
- Department of Infectious Diseases, Air Force Hospital of Southern Theatre Command, 801 Dongfeng East Rd, Guangzhou, Guangdong Province, 510602, China
| | - Ze-Ren Chen
- Department of Infectious Diseases, Air Force Hospital of Southern Theatre Command, 801 Dongfeng East Rd, Guangzhou, Guangdong Province, 510602, China
| | - Jian-Qi Lian
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd, Baqiao District, Xi'an, Shaanxi Province, 710038, China
| | - Shi-Hong Wu
- Department of Infectious Diseases, Yuncheng Central Hospital Affiliated to Shanxi Medical University, 3690 Hedong East Rd, Yuncheng, Shanxi Province, 044000, China.
| | - Li-Min Luo
- Department of Infectious Diseases, Air Force Hospital of Southern Theatre Command, 801 Dongfeng East Rd, Guangzhou, Guangdong Province, 510602, China.
| | - Wei-Lu Zhang
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 17 Changle West Rd, Xi'an, Shaanxi Province, 710032, China.
| | - Ye Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Rd, Baqiao District, Xi'an, Shaanxi Province, 710038, China.
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Wu J, Xie S, Ma Y, He X, Dong X, Shi Q, Wang Q, Li M, Yao N, Yao L. Entecavir for children and adults with chronic hepatitis B. Cochrane Database Syst Rev 2025; 4:CD015536. [PMID: 40260837 PMCID: PMC12012880 DOI: 10.1002/14651858.cd015536.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
RATIONALE Chronic hepatitis B is a major worldwide public health concern. Entecavir, one nucleos(t)ide analogue antiviral therapy option, is recommended as the first-line drug for chronic hepatitis B in many clinical guidelines. However, none of the guideline recommendations are based on the findings of a systematic review with meta-analysis, where entecavir versus no treatment or placebo are compared directly. OBJECTIVES To evaluate the benefits and harms of entecavir versus no treatment or placebo in children and adults with chronic hepatitis B, who are either hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, three other databases, online trial registries, and reference lists, and contacted authors. The latest search was on 19 July 2024. ELIGIBILITY CRITERIA We included randomised clinical trials comparing entecavir versus no treatment or placebo in children or adults, or both, with chronic hepatitis B, and irrespective of treatment history with other antiviral drugs and other viral co-infections. We allowed co-interventions when administered equally to all intervention groups. OUTCOMES The outcomes reported in this abstract and in the summary of findings table are all-cause mortality, health-related quality of life, and proportion of people with serious adverse events at the longest follow-up. RISK OF BIAS We used the Cochrane RoB 2 tool to assess risk of bias in the included trials. SYNTHESIS METHODS We used a random-effects model to meta-analyse outcome results, where possible, and presented the results as a risk ratio (RR) with 95% confidence interval (CI). Where there was considerable heterogeneity, we performed a narrative analysis. We used a fixed-effect model for sensitivity analysis. We used GRADE to evaluate the certainty of evidence. INCLUDED STUDIES We included 22 randomised clinical trials (published from 2005 to 2022) with 2940 participants diagnosed with chronic hepatitis B. All trials had a parallel-group design. The experimental intervention was oral entecavir, with a follow-up duration of 5 weeks to 228 weeks. The comparator in 12 trials was no treatment, and in 10 trials was placebo. Fourteen trials equally administered co-interventions to the trial participants in the entecavir and no treatment and placebo groups. One trial included participants between 14 years and 55 years of age, one trial included only children, 19 trials included only adults, and one trial did not provide the age of participants. SYNTHESIS OF RESULTS Twenty trials contributed data to the quantitative analysis. Ten trials (1379 participants) reported all-cause mortality with a mean follow-up duration of 48.9 weeks (range 5 to 100 weeks). The result was not estimable because no deaths occurred in any of the entecavir and no treatment or placebo groups. None of the trials provided data on health-related quality of life. We are very uncertain about the effect of entecavir versus no treatment or placebo on the proportion of people with serious adverse events (RR 0.66, 95% CI 0.33 to 1.32; absolute risk difference 22 fewer per 1000 (from 44 fewer to 21 more); 15 trials, 1676 participants; very low-certainty evidence). The mean follow-up duration was 58.4 weeks (range 5 weeks to 228 weeks). We downgraded the certainty of evidence for these outcomes to very low, mainly because the overall risk of bias in most trials was with some concerns or high, and serious imprecision (no events or few events). AUTHORS' CONCLUSIONS Given the issues of risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, we could not determine the effect of entecavir versus no treatment or placebo on critical outcomes such as all-cause mortality and serious adverse events. There is a lack of data on health-related quality of life. Given the first-line recommendation and wide usage of entecavir in people with chronic hepatitis B, further evidence on clinically important outcomes, analysed in this review, is needed. FUNDING This Cochrane review had no dedicated funding. REGISTRATION Registration: Entecavir for children and adults with chronic hepatitis B, CD015536 via DOI 10.1002/14651858.CD015536.
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Affiliation(s)
- Jing Wu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Shitong Xie
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Yanfang Ma
- Chinese EQUATOR Centre, Hong Kong Baptist University, Hong Kong, China
| | - Xiaoning He
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Xinyue Dong
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Qianling Shi
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Qi Wang
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Meixuan Li
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Naijuan Yao
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Yao
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
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Ortonne V, Bouvier-Alias M, Vo-Quang E, Cappy P, Ingiliz P, Leroy V, Pawlotsky JM, Chevaliez S. Performance evaluation of a fully automated deep sequencing platform for hepatitis B genotyping and resistance testing. J Antimicrob Chemother 2025; 80:919-926. [PMID: 39918840 DOI: 10.1093/jac/dkae418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/30/2024] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Treatment of chronic hepatitis B infection requires lifelong administration of nucleos(t)ide analogues with a high barrier to resistance and effective viral suppression. The major limitation of lifelong therapy is the possible selection of drug-resistant hepatitis B virus (HBV) strains. International Liver Society guidelines recommend that hepatitis B resistance testing must be performed by a reference laboratory. OBJECTIVES Performance of the deep sequencing-based ViroKey® SQ FLEX Genotyping Assay for the determination of HBV genotypes and resistance profiles were evaluated. PATIENTS AND METHODS Plasma samples collected from patients with chronic hepatitis B have been sequenced by two methods including Sanger (population) sequencing of a portion of the P/S overlapping gene and the deep sequencing-based ViroKey® SQ FLEX Genotyping Assay (Vela Diagnostics). RESULTS A high concordance rate with population sequencing was found regardless of HBV genotypes. Deep sequencing with the Sentosa platform was more sensitive than population sequencing in detecting minor variant populations. CONCLUSIONS The deep sequencing-based ViroKey® SQ FLEX Genotyping Assay can be confidently used in clinical practice for hepatitis B genotyping and resistance testing.
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Affiliation(s)
- Valérie Ortonne
- Department of Virology, French National Reference Center for Hepatitis B, C and D Viruses, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
| | - Magali Bouvier-Alias
- Department of Virology, French National Reference Center for Hepatitis B, C and D Viruses, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
| | - Erwan Vo-Quang
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
- Department of Hepatology, Hôpital Henri Mondor (AP-HP), Créteil, France
| | - Pierre Cappy
- Department of Virology, French National Reference Center for Hepatitis B, C and D Viruses, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
| | - Patrick Ingiliz
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
- Department of Hepatology, Hôpital Henri Mondor (AP-HP), Créteil, France
| | - Vincent Leroy
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
- Department of Hepatology, Hôpital Henri Mondor (AP-HP), Créteil, France
| | - Jean-Michel Pawlotsky
- Department of Virology, French National Reference Center for Hepatitis B, C and D Viruses, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
| | - Stéphane Chevaliez
- Department of Virology, French National Reference Center for Hepatitis B, C and D Viruses, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- 'Team Viruses, Hepatology, Cancer', Institut de Recherche Biomédicale, INSERM U955, Créteil, France
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Xiang YJ, Wang K, Qin YY, Liu ZH, Yu HM, Cheng YQ, Gu HY, Feng JK, Ni QZ, Zhu HF, Yang SY, Lin EH, Cai WT, Cheng DH, Tang YF, Zhang F, Liang C, Zhou HK, Wu W, Li JJ, Shan YF, Cheng SQ. Trajectories of postoperative hepatitis B virus (HBV) DNA and HBV-related hepatocellular carcinoma outcomes. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109492. [PMID: 39615296 DOI: 10.1016/j.ejso.2024.109492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 11/08/2024] [Accepted: 11/22/2024] [Indexed: 02/10/2025]
Abstract
BACKGROUND Preoperative hepatitis B virus (HBV) DNA level has been shown to correlate with the prognosis of patients with HBV-associated hepatocellular carcinoma (HCC) following liver resection, but its dynamic changes have not been reported. The aim of this longitudinal multicenter retrospective observational study was to describe the trajectory of HBV DNA after R0 liver resection in patients receiving antiviral therapy and to investigate its impact on clinical outcomes. METHODS This study included patients with HBV-related HCC from nine hospitals in China who received antiviral therapy and R0 hepatectomy between 2015 and 2016. A latent class growth mixed model (LCGMM) was applied to group the trajectories of HBV DNA changes. The relative importance of each variable to predict survival was evaluated using the χ2. RESULTS Six hundred and eighty-four patients with HCC who met the inclusion exclusion criteria were included. Patients were divided into 5 trajectories of HBV DNA changes using LCGMM. By combining subgroups with similar survival characteristics, patients were reclassified into three groups: slow decline, slow zeroing, and fast zeroing group, the 5-year OS rates are 34.5 %, 53.0 %, 70.9 %, respectively. Multifactorial COX regression results showed that ALBI grade, HBV reactivation, cirrhosis, maximum tumor diameter, microvascular invasion, and HBV DNA trajectory groups were independent risk factors for OS. CONCLUSIONS HBV DNA trajectories were associated with OS for patients with HBV-related HCC after R0 liver resection, and it is necessary to receive antiviral therapy and to monitor HBV status regularly.
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Affiliation(s)
- Yan-Jun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ying-Yi Qin
- Department of Health Statistics, Naval Medical University, Shanghai, China
| | - Zong-Han Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hong-Ming Yu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yu-Qiang Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hong-Yi Gu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jin-Kai Feng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Qian-Zhi Ni
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hong-Fei Zhu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Shi-Ye Yang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - En-Hua Lin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wen-Tao Cai
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dong-Hui Cheng
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yu-Fu Tang
- Department of Hepatobiliary Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Fan Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Binzhou Medical College, Binzhou, China
| | - Chao Liang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong-Kun Zhou
- The First Hospital of Jiaxing Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Wei Wu
- Department of Hepatology, The Sixth People's Hospital of Shenyang, Shenyang, China
| | - Jing-Jing Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yun-Feng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
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Wang J, Zhang Z, Yin S, Zhang S, Zhu L, Pan Y, Fan T, Cao F, Xiong Y, Jiang C, Wang G, Yang Y, Jia B, Liu J, Xia J, Yan X, Li J, Zhu C, Liu X, Chen Y, Wu C, Huang R. Favourable Prognosis of Patients With Untreated HBeAg-Negative Chronic Hepatitis B Virus Infection With HBsAg < 100 IU/mL. Aliment Pharmacol Ther 2025; 61:472-480. [PMID: 39523981 DOI: 10.1111/apt.18383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/12/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Serum hepatitis B surface antigen (HBsAg) < 100 IU/mL has been recently proposed as one of the key criteria of 'partial cure' in patients with chronic hepatitis B virus (HBV) infection. We analysed the clinical prognosis of hepatitis B e antigen (HBeAg)-negative untreated patients with HBsAg < 100 IU/mL and normal alanine aminotransferase (ALT) levels. METHODS Five hundred and twenty-one untreated patients with HBeAg negativity, HBsAg < 100 IU/mL and normal ALT levels were included from three hospitals. Spontaneous HBsAg seroclearance, phase transition, liver fibrosis progression and hepatocellular carcinoma (HCC) development were analysed. RESULTS The median age was 43.0 years, and 62.2% of the patients were male. After a median follow-up of 25.0 months, 52 (10.0%) patients achieved spontaneous HBsAg seroclearance. The annual HBsAg seroclearance rate is 4.2%. Patients with baseline HBsAg ≤ 10 IU/mL (adjusted hazard ratio [aHR] = 3.490, p < 0.001) and male sex (aHR = 1.980, p = 0.041) were more likely to achieve HBsAg seroclearance. Only 4 (0.8%) and 23 (4.8%) patients transitioned to the immune escape phase and HBeAg-negative indeterminate phase, respectively. Baseline serum HBsAg > 10 IU/mL (aHR = 3.846, p = 0.034) and detectable HBV DNA (aHR = 2.672, p = 0.023) were associated with transition to the HBeAg-negative indeterminate phase. No patient developed HCC or had fatal outcomes. CONCLUSIONS HBeAg-negative patients with serum HBsAg < 100 IU/mL and normal ALT levels had a favourable prognosis. HBsAg ≤ 10 IU/mL and male sex were associated with a higher rate of HBsAg seroclearance, while HBsAg > 10 IU/mL and detectable HBV DNA were associated with a higher risk of transition to the indeterminate phase.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Zhiyi Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shaoqiu Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yifan Pan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tao Fan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Fei Cao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ye Xiong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yue Yang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Bei Jia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xingxiang Liu
- Department of Clinical Laboratory, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China
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Kim HR, Kang SH, Yim HJ, Suh SJ, Jung YK, Kim JH, Seo YS, Yeon JE, Byun KS. Need of Treatment Modification During Entecavir Therapy in Patients with Chronic Hepatitis B: Long-Term Follow-Up Results for 120 Months. Microorganisms 2025; 13:218. [PMID: 40005585 PMCID: PMC11857378 DOI: 10.3390/microorganisms13020218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
Entecavir (ETV) may have limited antiviral efficacy in chronic hepatitis B (CHB) patients with a high baseline viral load, especially in cases of partial virologic response (PVR). This study evaluated the outcomes of prolonged ETV monotherapy, given the lack of clear evidence favoring continuation or combination therapy in such scenarios. We included 188 treatment-naïve patients on ETV 0.5 mg and compared antiviral responses between high viral load (HVL, ≥7 log10 IU/mL) and non-HVL groups for over up to 120 months in this study. Compared to the non-HVL group, the HVL group exhibited a lower cumulative virologic response (VR, <20 IU/mL) during the 10-year therapy period (p < 0.01). Antiviral resistance to entecavir (rtS202G + rtM204V + rtL180M) developed in three out of 90 patients in the HVL group. Patients with complete response at 6 months had a 100% likelihood of achieving VR, while 83.9% of patients with PVR at 6 months achieved VR by month 120 (p < 0.01). Multivariate analysis revealed that baseline HVL was a significant predictor of long-term VR at 120 months. In conclusion, CHB patients with baseline HVL and PVR at 6 months are prone to ETV resistance and inadequate response, warranting a modification in treatment strategy.
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Affiliation(s)
| | | | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Republic of Korea; (H.R.K.); (S.H.K.); (S.J.S.); (Y.K.J.); (J.H.K.); (Y.S.S.); (J.E.Y.); (K.S.B.)
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7
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Chu YD, Hsu CW, Ho PH, Chiou CY, Lin CL, Liang KH, Lai MW, Yeh CT. Evolution of hepatitis B virus polymerase and surface genes in patients receiving finite antiviral therapy. J Gastroenterol Hepatol 2025; 40:265-273. [PMID: 39500510 DOI: 10.1111/jgh.16791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND AND AIM Hepatitis B virus (HBV) reactivation could develop after withdrawal following a finite course of nucleoside analog (NA) therapy, leading to virological and clinical relapses. The genetic heterogeneity in the HBV surface and polymerase genes during finite NA therapy has not been carefully studied. METHODS Seven chronic HBV-infected patients experiencing relapses following entecavir (ETV; n = 5; Patients 1 to 5) or tenofovir disoproxil fumarate (TDF; n = 2; Patients 6 and 7) withdrawal were included. Sera obtained before treatment and at relapses were retrieved and submitted for DNA extraction and amplicon-specific deep sequencing. RESULTS ETV-treated patients had a longer time-to-relapse than that of TDF-treated patients (P = 0.0357). No drug-resistance related polymerase mutation was detected during relapses, except for a low percentage (1.4%) of rtM204I mutation in Patient 1. Two surface truncation mutations (sW216*; 40.9% and sW182*; 4.7%) detected before treatment in two TDF-treated patients (Patients 6 and 7, respectively) were overtaken by the wild types during subsequent drug-withdrawal-related relapses. The simultaneous presence of sG44E (T-cell epitope) and sE164G (B-cell epitope) mutations was associated with failure of HBV e antigen (HBeAg) seroclearance in ETV-treated patients. CONCLUSIONS In conclusion, HBV genome continues to evolve during the courses of finite antiviral therapies. Pre-existing surface truncation mutations can be overtaken by the wild types after relapses. The sG44E/sE164G mutations are associated with failure of HBeAg seroclearance.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Pei-Huan Ho
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chih-Yung Chiou
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Liver Research Unit and Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Kung-Hao Liang
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Division of Pediatric Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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8
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Wang J, Zhu L, Zhang S, Zhang Z, Fan T, Cao F, Xiong Y, Pan Y, Li Y, Jiang C, Yin S, Tong X, Xiong Y, Xia J, Yan X, Liu Y, Liu X, Chen Y, Li J, Zhu C, Wu C, Huang R. Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA. Emerg Microbes Infect 2024; 13:2339944. [PMID: 38584592 PMCID: PMC11022914 DOI: 10.1080/22221751.2024.2339944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 04/03/2024] [Indexed: 04/09/2024]
Abstract
Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Shaoqiu Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Zhiyi Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Tao Fan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Fei Cao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Ye Xiong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Yifan Pan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yuanyuan Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Chao Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, People’s Republic of China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Yali Xiong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
| | - Yong Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Xingxiang Liu
- Department of Clinical Laboratory, Huai’an No. 4 People’s Hospital, Huai’an, People’s Republic of China
| | - Yuxin Chen
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, People’s Republic of China
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9
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Gotchev D, Chen S, Dugan B, Dorsey BD, Wang X, Sheraz M, Kowalski R, Liu F, Tang S, Chiu T, Harasym T, Graves IE, Thi EP, Mason JD, Overholt N, Dugyala R, Lam AM, Cole AG, Sofia MJ. Structure-Activity Relationships and Discovery of ( S)-5-( tert-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2',1':2,3]imidazo[4,5- h]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer. J Med Chem 2024; 67:20467-20494. [PMID: 39513566 DOI: 10.1021/acs.jmedchem.4c01928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Lowering hepatitis B surface antigen (HBsAg) levels from covalently closed circular DNA (cccDNA) and the integrated genome could reduce the persistence of hepatitis B virus (HBV) infection. Since HBV replication occurs in the liver and to ameliorate the peripheral neuropathy observed with a first-generation tricyclic 4-pyridone PAPD5/7 inhibitor (AB-452) having high systemic exposure, we focused on increasing the hepatocyte concentration and reducing plasma levels. Optimization of a novel series of PAPD5/7 inhibitors that decrease HBsAg levels led to the tetracyclic 2-pyridone AB-161, which was similarly potent to AB-452 in vitro and in vivo but showed dramatically higher rodent liver-to-plasma ratios. There were no neurobehavioral effects with AB-161 in dogs up to 45 mg/kg after 60 days, unlike with AB-452, where these were observed at lower doses by day 14. AB-161 was then advanced into 90-day GLP toxicology studies, where the improved neurotoxicity profile persisted, but reproductive issues emerged, leading to discontinuation.
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Affiliation(s)
- Dimitar Gotchev
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Shuai Chen
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Benjamin Dugan
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Bruce D Dorsey
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Xu Wang
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Muhammad Sheraz
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Rose Kowalski
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Fei Liu
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Sunny Tang
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Tim Chiu
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Troy Harasym
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Ingrid E Graves
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Emily P Thi
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Jeremy D Mason
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Nathan Overholt
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Ravi Dugyala
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Angela M Lam
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Andrew G Cole
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
| | - Michael J Sofia
- Arbutus Biopharma, Warminster, Pennsylvania 18974, United States
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10
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McCoullough LC, Fareh M, Hu W, Sozzi V, Makhlouf C, Droungas Y, Lee CL, Takawy M, Fabb SA, Payne TJ, Pouton CW, Netter HJ, Lewin SR, Purcell DF, Holmes JA, Trapani JA, Littlejohn M, Revill PA. CRISPR-Cas13b-mediated suppression of HBV replication and protein expression. J Hepatol 2024; 81:794-805. [PMID: 38815932 DOI: 10.1016/j.jhep.2024.05.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 04/19/2024] [Accepted: 05/16/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND & AIMS New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression. METHODS Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. RESULTS Our HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line. CONCLUSIONS Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection. IMPACT AND IMPLICATIONS Owing to the limitations of current antiviral therapies for hepatitis B, there is an urgent need for new treatments that target multiple aspects of the HBV replication cycle to improve rates of functional cure. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression, paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.
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Affiliation(s)
- Laura C McCoullough
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Mohamed Fareh
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Wenxin Hu
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Vitina Sozzi
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Christina Makhlouf
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Yianni Droungas
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Chee Leng Lee
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Mina Takawy
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Stewart A Fabb
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Thomas J Payne
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Colin W Pouton
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Hans J Netter
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sharon R Lewin
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
| | - Damian Fj Purcell
- Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Jacinta A Holmes
- Department of Gastroenterology, St. Vincent's Hospital, Melbourne, Victoria, Australia
| | - Joseph A Trapani
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
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11
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Ho AS, Chang J, Lee SD, Sie ZL, Shih HF, Yeh C, Peng CL, Dev K, Cheng CC. Nucleos(t)ide analogues potentially activate T lymphocytes through inducing interferon expression in hepatic cells and patients with chronic hepatitis B. Sci Rep 2024; 14:25286. [PMID: 39455685 PMCID: PMC11511960 DOI: 10.1038/s41598-024-76270-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Chronic hepatitis B (CHB) leads to liver inflammation and dysfunction, resulting in liver fibrosis and cancer. Nucleos(t)ide analogues (NAs), inhibitors of hepatitis B virus (HBV), specifically suppress HBV replication. We proposed that immune modulation benefits seroconversion by HBsAg loss. However, activation of T lymphocytes also deteriorates hepatic inflammation. Therefore, we intended to investigate the T cell status and its relationship with hepatic functions in CHB patients treated with NAs. Serum markers, including liver function markers AST, ALT, and HBV-infected markers HBV DNA, HBsAg, HBeAg, and HBsAb were measured in the clinical routine. The T cell levels and markers, including CD69, CD107a, CXCR3, and PD-1 were investigated using flow cytometry. Meanwhile, IFNγ, IL-2, and CXCL10 as immune activation markers in the PBMCs were investigated using qPCR. To validate the effects of NAs on T cell status, qPCR and flow cytometry were used to investigate the gene expression in the HepG2 and PLC5 cells treated with NAs, and in the healthy PBMCs treated with the cell-cultured supernatant. We found that NAs significantly suppressed HBV DNA and reduced AST and ALT levels in the CHB patients. Meanwhile, AST and ALT were both positively correlated with activation marker CD107a in CD8+ T cells. In addition, we found that the CHB patients with seroconversion exhibited a higher CD4/CD8 ratio (p < 0.05) compared to non-seroconversion. We demonstrated that NAs potentially induced IFNs and PD-L1 expression in HepG2 and PLC5 cells. Moreover, the collected supernatant from NAs-treated HepG2 significantly activated PBMCs. This study revealed that the reduction of HBV by NAs may be the reason leading to less AST and ALT levels. We further demonstrated that NAs induced IFN expression in hepatic cells to potentially activate T lymphocytes, which was positively associated with AST and ALT levels in the CHB patients. The results may explain the phenomena in clinical that when the virus is reactivated by aborted use of NAs, it causes consequent T cells-mediated severe acute-on-chronic liver injury.
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Affiliation(s)
- Ai-Sheng Ho
- Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, 112, Taiwan
| | - Jungshan Chang
- Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
| | - Shou-Dong Lee
- Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, 112, Taiwan
| | - Zong-Lin Sie
- Research Center of Radiation Medicine, Chang Gung University, Taoyuan, 333, Taiwan
| | - Hui-Fen Shih
- Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, 112, Taiwan
| | - Chun Yeh
- Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, 112, Taiwan
| | - Cheng-Liang Peng
- Department of Isotope Application Research, National Atomic Research Institute, Taoyuan, 325, Taiwan
| | - Kapil Dev
- Research Center of Radiation Medicine, Chang Gung University, Taoyuan, 333, Taiwan
| | - Chun-Chia Cheng
- Research Center of Radiation Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
- Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan.
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12
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Lani L, Stefanini B, Trevisani F. Surveillance for Hepatocellular Carcinoma in Patients with Successfully Treated Viral Disease of the Liver: A Systematic Review. Liver Cancer 2024; 13:376-388. [PMID: 39114761 PMCID: PMC11305665 DOI: 10.1159/000535497] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 11/23/2023] [Indexed: 08/10/2024] Open
Abstract
Background Surveillance for hepatocellular carcinoma (HCC) has been proven to increase the proportion of tumors detected at early stages and the chance of receiving curative therapies, reducing mortality by about 30%. Summary Current recommendations consist of a semi-annual abdominal ultrasound with or without serum alpha-fetoprotein measurement in patients with cirrhosis and specific subgroups of populations with chronic viral hepatitis. Antiviral therapies, such as nucleot(s)ide analogs that efficiently suppress the replication of hepatitis B virus (HBV) and direct-acting antiviral drugs able to eliminate the hepatitis C virus (HCV) in >90% of patients, have radically changed the outcomes of viral liver disease and decreased, but not eliminated, the risk of HCC in both cirrhotic and non-cirrhotic patients. HCC risk is a key starting point for implementing a cost-effective surveillance and should also guide the decision-making process concerning its modality. As the global number of effectively treated viral patients continues to rise, there is a pressing need to identify those for whom the benefit-to-harm ratio of surveillance is favorable and to determine how to conduct cost-effective screening on such patients. Key Messages This article addresses this topic and attempts to determine which patients should continue HCC surveillance after HBV suppression or HCV eradication, based on cost-effectiveness principles and the fact that HCC risk declines over time. We also formulate a proposal for a surveillance algorithm that switches the use of surveillance for HCC from the "one-size-fits-all" approach to individualized programs based on oncologic risk (precision surveillance).
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Affiliation(s)
- Lorenzo Lani
- Unit of Semeiotics, Liver, and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Benedetta Stefanini
- Unit of Semeiotics, Liver, and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Franco Trevisani
- Unit of Semeiotics, Liver, and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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13
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Zheng D, Cheng C, Tang Y, Fang Z, Gao X, Chen Y, You Q, Wang K, Zhou H, Lan Z, Sun J. Circulating metabolites are associated with persistent elevations of ALT in patients with chronic hepatitis B with complete viral suppression. J Med Virol 2024; 96:e29723. [PMID: 38828911 DOI: 10.1002/jmv.29723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 06/05/2024]
Abstract
Hepatitis B virus (HBV) can be completely suppressed after antiviral treatment; however, some patients with chronic hepatitis B (CHB) exhibit elevated alanine aminotransferase (ALT) levels and sustained disease progression. This study provides novel insights into the mechanism and potential predictive biomarkers of persistently elevated ALT (PeALT) in patients with CHB after complete viral inhibition. Patients having CHB with undetectable HBV DNA at least 12 months after antiviral treatment were enrolled from a prospective, observational cohort. Patients with PeALT and persistently normal ALT (PnALT) were matched 1:1 using propensity score matching. Correlations between plasma metabolites and the risk of elevated ALT were examined using multivariate logistic regression. A mouse model of carbon tetrachloride-induced liver injury was established to validate the effect of key differential metabolites on liver injury. Of the 1238 patients with CHB who achieved complete viral suppression, 40 (3.23%) had PeALT levels during follow-up (median follow-up: 2.42 years). Additionally, 40 patients with PnALT levels were matched as controls. Ser-Phe-Ala, Lys-Ala-Leu-Glu, 3-methylhippuric acid, 3-methylxanthine, and 7-methylxanthine were identified as critical differential metabolites between the two groups and independently associated with PeALT risk. Ser-Phe-Ala and Lys-Ala-Leu-Glu levels could be used to discriminate patients with PeALT from those with PnALT. Furthermore, N-acetyl- l-methionine (NALM) demonstrated the strongest negative correlation with ALT levels. NALM supplementation alleviated liver injury and hepatic necrosis induced by carbon tetrachloride in mice. Changes in circulating metabolites may contribute to PeALT levels in patients with CHB who have achieved complete viral suppression after antiviral treatment.
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Affiliation(s)
- Dekai Zheng
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Changhao Cheng
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanhua Tang
- Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhixin Fang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuelian Gao
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuchuan Chen
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiuhong You
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kaifeng Wang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Heqi Zhou
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhixian Lan
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Hepatology, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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14
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Ignat MD, Balta AAS, Barbu RE, Draganescu ML, Nechita L, Voinescu DC, Nechita A, Stefanopol IA, Busila C, Baroiu L. Antiviral Therapy of Chronic Hepatitis B Virus between Present and Future. J Clin Med 2024; 13:2055. [PMID: 38610820 PMCID: PMC11012273 DOI: 10.3390/jcm13072055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/31/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Background/Objectives: The objective of this study was to analyze the results of clinical trials regarding long-term antiviral therapies in chronic hepatitis with HBV to compare current therapeutic protocols and to analyze the results of preliminary studies with new antiviral therapies for HBV. Methods: Clinical studies and meta-analyses from PubMed, Google Scholar, and Research Gate from 2011 to 2024 were analyzed on patients undergoing chronic antiviral therapy for HBV, and a retrospective observational study performed in our clinic on a group of 76 patients undergoing chronic therapy with entecavir was presented. Also, a summary of the results of preliminary studies with various innovative antiviral molecules for HBV was performed. Results: The results of extensive clinical trials reveal that current therapies for chronic HBV are well tolerated and maintain good viral suppression if the patient is adherent to therapy. Innovative therapies aim to eliminate HBsAg and, thus, significantly shorten the duration of treatment, and the preliminary results of the studies are promising. Conclusions: Being an asymptomatic condition that requires life-long therapy, adherence to therapy is a real problem. Also, the risk of decompensation of liver cirrhosis and adenocarcinoma remains important in these patients. Future research is needed to perfect some antiviral therapy schemes that shorten the treatment period but also decrease the rate of progression towards decompensated cirrhosis and liver adenocarcinoma.
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Affiliation(s)
- Mariana Daniela Ignat
- Doctoral School of Biomedical Sciences, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.D.I.); (R.E.B.)
| | | | - Raisa Eloise Barbu
- Doctoral School of Biomedical Sciences, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.D.I.); (R.E.B.)
| | - Miruna Luminita Draganescu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Cuv. Parascheva’ Clinical Hospital of Infectious Diseases, 800179 Galati, Romania
| | - Luiza Nechita
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Apostol Andrei’ Clinical Emergency County Hospital, 800578 Galati, Romania
| | - Doina Carina Voinescu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Apostol Andrei’ Clinical Emergency County Hospital, 800578 Galati, Romania
| | - Aurel Nechita
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania;
| | - Ioana Anca Stefanopol
- ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania;
- Clinical Surgical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania
| | - Camelia Busila
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania;
| | - Liliana Baroiu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunarea de Jos’ University, 800008 Galati, Romania; (M.L.D.); (L.N.); (D.C.V.); (A.N.); (C.B.); (L.B.)
- ‘Sf. Cuv. Parascheva’ Clinical Hospital of Infectious Diseases, 800179 Galati, Romania
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15
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Lam R, Lim JK. Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B: A comprehensive review of phases II and III therapeutic agents. World J Hepatol 2024; 16:331-343. [PMID: 38577537 PMCID: PMC10989302 DOI: 10.4254/wjh.v16.i3.331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/23/2024] [Accepted: 02/29/2024] [Indexed: 03/27/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects over 295 million people globally and an estimated 1.6 million people in the United States. It is associated with significant morbidity and mortality due to cirrhosis, liver failure, and liver cancer. Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression, which in turn has been associated with a decreased risk of liver complications. However, current antiviral regimens are limited by concerns with adverse effects, adherence, resistance, long-term treatment, and ongoing risk for liver events. Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen (HBsAg) loss and suppression of HBV DNA. Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B, including core/capsid inhibitors, entry inhibitors, RNA interference (siRNA/ASO), HBsAg inhibitors, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.
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Affiliation(s)
- Robert Lam
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, United States
| | - Joseph K Lim
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, United States.
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16
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Ogawa E, Jun DW, Toyoda H, Hsu YC, Yoon EL, Ahn SB, Yeh ML, Do S, Trinh HN, Takahashi H, Enomoto M, Kawada N, Yasuda S, Tseng CH, Kawashima K, Lee HA, Inoue K, Haga H, Do AT, Maeda M, Hoang JH, Cheung R, Ueno Y, Eguchi Y, Furusyo N, Yu ML, Tanaka Y, Nguyen MH. Increased spine bone density in patients with chronic hepatitis B switched to tenofovir alafenamide: A prospective, multinational study. Aliment Pharmacol Ther 2024; 59:239-248. [PMID: 37882252 DOI: 10.1111/apt.17785] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/31/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. AIMS To assess the treatment and renal/bone safety outcomes following the switch to TAF. METHODS We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T-scores (L-spine) by bone absorptiometry by 24 months after switch to TAF. RESULTS We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T-score improved significantly from -1.43 ± 1.36 to -1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9-89.5 ± 16.3 mL/min/1.73 m2 , p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T-score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T-score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). CONCLUSIONS At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University, College of Medicine, Seoul, South Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, South Korea
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Eileen L Yoon
- Department of Internal Medicine, Hanyang University, College of Medicine, Seoul, South Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, South Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, South Korea
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Son Do
- Digestive Health Associates of Texas, Dallas, Texas, USA
| | - Huy N Trinh
- San Jose Gastroenterology, San Jose, California, USA
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Saga, Japan
- Division of Metabolism and San Jose Gastroenterology Endocrinology, Saga University Faculty of Medicine, Saga, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Keigo Kawashima
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Kaori Inoue
- Liver Center, Saga University Hospital, Saga, Japan
| | - Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Ai-Thien Do
- Digestive Health Associates of Texas, Dallas, Texas, USA
| | - Mayumi Maeda
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Joseph H Hoang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yuichiro Eguchi
- Liver Center, Saga University Hospital, Saga, Japan
- Locomedical General Institute, Locomedical Eguchi Hospital, Saga, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Center of Excellence for Metabolic Associated Fatty Liver Disease, School of Medicine, College of Medicine, Kaohsiung, Taiwan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
- Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA
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17
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Peng W, Yi M, Qi X, Qi W, Li C, Wen T. The effect of switch therapy to tenofovir versus entecavir maintenance on recurrence of hepatocellular carcinoma after surgery (SWITE): study protocol for a randomized controlled trial. Trials 2023; 24:781. [PMID: 38042834 PMCID: PMC10693690 DOI: 10.1186/s13063-023-07822-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 11/22/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND Antiviral therapy has been reported to be associated with lower recurrence rate of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV) infection. While entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were both recommended as first-line therapies for HBV patients, recent retrospective studies proposed a lower incidence rate of HCC occurrence or recurrence in those receiving TDF compared ETV. However, the survival benefits of switching to TDF therapy after prolonged ETV treatment before surgery remain uncertain. We delineate the rationale and design of SWITE, a randomized, open-label, phase III trial contrasting TDF switch therapy versus ETV maintenance in HBV-related HCC patients. METHODS AND ANALYSIS This is a prospective, randomized, controlled, single-center study with two parallel groups of patients with HBV-related HCC who have received long-term ETV therapy before surgery. West China Hospital will enroll 238 patients, randomized in a 1:1 ratio to TDF switch therapy or ETV maintenance after surgery. The primary endpoint of this study is 3-year recurrence free survival (RFS), with the secondary endpoint being 3-year overall survival (OS) after curative surgery of HCC. Safety events will be diligently recorded. ETHICS AND DISSEMINATION The study protocol aligns with the ethical guidelines of the 1975 Declaration of Helsinki. It was approved by ethics committee of West China Hospital (approval number: 2022-074) and was registered with chictr.org.cn (chiCTR2200057867). Informed consent will be obtained from all participants. The results of this trial will be published in peer-reviewed journals and presentations at national and international conferences relevant to this topic. TRIAL REGISTRATION chiCTR2200057867 . Date of registration is March 20 2022.
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Affiliation(s)
- Wei Peng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
- Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mengshi Yi
- Deparment of Hepatobiliary Surgery, the First Affiliated Hospital of Army Medical University, Chongqing, China
| | - Xin Qi
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Weili Qi
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chuan Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tianfu Wen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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18
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Choi J, Choi WM, Lim YS. Are the New Nucleos(t)ide Analogs Better than the Old Nucleos(t)ide Analogs? Clin Liver Dis 2023; 27:809-818. [PMID: 37778771 DOI: 10.1016/j.cld.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
In treatment-naïve patients with chronic hepatitis B virus (HBV) infection, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide have a minimal or no risk of drug-resistance. These 3 nucleos(t)ide analog agents are highly potent inducing high rate of virologic response (reducing serum HBV DNA to levels undetectable by polymerase chain reaction assays) in most treatment-naïve patients. Our randomized trials have demonstrated that monotherapy with TDF can provide a successful virological response in most of the heavily pretreated patients with multidrug resistance to ETV or adefovir.
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Affiliation(s)
- Jonggi Choi
- Department Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Won-Mook Choi
- Department Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Young-Suk Lim
- Department Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
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19
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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20
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Elalouf A. Infections after organ transplantation and immune response. Transpl Immunol 2023; 77:101798. [PMID: 36731780 DOI: 10.1016/j.trim.2023.101798] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 01/08/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023]
Abstract
Organ transplantation has provided another chance of survival for end-stage organ failure patients. Yet, transplant rejection is still a main challenging factor. Immunosuppressive drugs have been used to avoid rejection and suppress the immune response against allografts. Thus, immunosuppressants increase the risk of infection in immunocompromised organ transplant recipients. The infection risk reflects the relationship between the nature and severity of immunosuppression and infectious diseases. Furthermore, immunosuppressants show an immunological impact on the genetics of innate and adaptive immune responses. This effect usually reactivates the post-transplant infection in the donor and recipient tissues since T-cell activation has a substantial role in allograft rejection. Meanwhile, different infections have been found to activate the T-cells into CD4+ helper T-cell subset and CD8+ cytotoxic T-lymphocyte that affect the infection and the allograft. Therefore, the best management and preventive strategies of immunosuppression, antimicrobial prophylaxis, and intensive medical care are required for successful organ transplantation. This review addresses the activation of immune responses against different infections in immunocompromised individuals after organ transplantation.
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Affiliation(s)
- Amir Elalouf
- Bar-Ilan University, Department of Management, Ramat Gan 5290002, Israel.
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21
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Zhang Q, Liu X, Pang X, Wang H, Du J, Ren H, Hu P. Recovery of host adaptive immune function promoted the reduction of hepatitis B surface antigen in nucleoside analog-experienced chronic hepatitis B patients with low hepatitis B surface antigen levels. Cytokine 2023; 164:156140. [PMID: 36738524 DOI: 10.1016/j.cyto.2023.156140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/21/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023]
Abstract
Hepatitis B surface antigen (HBsAg) seroclearance is an optimal therapeutic endpoint, as it reflects the amount of covalently closed circular DNA. The exact mechanisms that contribute to HBsAg reduction are not completely understood. We evaluated adaptive immunity in nucleoside analog-experienced chronic hepatitis B (CHB) patients with low HBsAg levels who received oral antiviral therapy. One hundred and ninety-five CHB patients had hepatitis B virus (HBV) DNA ≤ 1000 IU/ml and HBsAg < 3000 IU/ml for longer than one year of antiviral therapy. According to HBsAg levels, they were divided into Group 1 (HBsAg reduction ≥ 0.5 log10) and Group 2 (HBsAg reduction < 0.5 log10). Cytokines, adaptive immune cells, and molecular markers in peripheral blood were detected at follow-up times. In total, 38 (19.5%) of the 195 patients achieved HBsAg reduction ≥ 0.5 log10. IL4, IL5, IL10, TGF β, IL17, and PD-1 decreased gradually in these patients. HBsAg reduction had a link to the change in ICOSL+CD19+ B cells and CD40L+CXCR5+CD4+ Tfh cells. More CD8+ naive T lymphocytes differentiated into CD4+ TCMs, CD8+ TCMs and CD8+ TEMs in Group 1. Meanwhile, Group 1 exhibited elevated Th1 and Th1/Th2 levels and reduced levels of Treg versus those in Group 2. With the reduction in HBsAg, the imbalance of T-cell subsets was partially corrected; the immune activity of T cells was enhanced, and the state of immune exhaustion was alleviated to a certain extent.
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Affiliation(s)
- Qian Zhang
- Department of Infectious Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China; Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqing Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xicheng Pang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huimin Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jinjie Du
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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22
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Yost CC, Jimenez DC, Weber MP, Maynes EJ, Belden KA, Tchantchaleishvili V, Massey HT, Sass DA, Rame JE, Zurlo JJ, Aburjania N. Hepatitis B in Heart Transplant Donors and Recipients: A Systematic Review and Meta-Analysis. J Surg Res 2023; 283:1078-1090. [PMID: 36914999 DOI: 10.1016/j.jss.2022.10.078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/13/2022] [Accepted: 10/19/2022] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Expanding the heart donor pool to include patients with hepatitis B virus (HBV) could help ameliorate the organ shortage in heart transplantation. We performed a systematic review and meta-analysis to evaluate the management and recipient outcomes of D+/R- and D-/R+ heart transplants. METHODS An electronic search was performed to identify all relevant studies published on heart transplants involving HBV+ donors and/or HBV+ recipients. A comparison was performed between two groups where heart transplants were performed a) D+/R- (n = 98) versus b) D-/R+ (n = 65). RESULTS Overall, 13 studies were selected, comprising 163 patients. Mean patient age was 55 y (95% CI: 39, 78) and 79% (69, 86) were male. Active post-transplant HBV infection requiring antiviral treatment occurred in 11% (1, 69) of D+/R- recipients and 33% (9, 71) of D-/R+ recipients. Post-transplant antiviral therapy was given to 80% (6, 100) of D+/R- recipients compared to 72% (42, 90) of D-/R+ recipients (P = 0.84). Hepatitis-related mortality was observed in no D+/R- recipients and 7% (2, 27) of D-/R+ recipients. Survival 1-y post-transplant was comparable between both groups at 83% (83, 92) and 81% (61, 92) for D+/R- and D-/R+ transplants, respectively. CONCLUSIONS Our review found that HBV D+/R- heart transplantation was associated with fewer active hepatitis infections and lower hepatitis-related mortality than D-/R+ transplantation, with comparable survival at 1 y. Additional studies utilizing HBV nucleic acid testing (NAT) to compare outcomes with HBsAg+ and anti-HBc+ donors are crucial to reach more definitive conclusions about the risk of donor-derived infections in this context.
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Affiliation(s)
- Colin C Yost
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Diana C Jimenez
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Matthew P Weber
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Elizabeth J Maynes
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Katherine A Belden
- Division of Infectious Diseases, Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - H Todd Massey
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - David A Sass
- Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - J Eduardo Rame
- Division of Cardiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - John J Zurlo
- Division of Infectious Diseases, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Nana Aburjania
- Division of Infectious Diseases, Thomas Jefferson University, Philadelphia, Pennsylvania.
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23
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Li P, Liang X, Luo J, Li J, Xin J, Jiang J, Shi D, Lu Y, Hassan HM, Zhou Q, Hao S, Zhang H, Wu T, Li T, Yao H, Ren K, Guo B, Zhou X, Chen J, He L, Yang H, Hu W, Ma S, Li B, You S, Xin S, Chen Y, Li J, Chinese Group on the Study of Severe Hepatitis B (COSSH). Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2023; 32:100638. [PMID: 36793753 PMCID: PMC9923183 DOI: 10.1016/j.lanwpc.2022.100638] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/22/2022] [Accepted: 10/20/2022] [Indexed: 11/12/2022]
Abstract
BACKGROUND Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. METHODS Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. FINDINGS In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. INTERPRETATION COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. FUNDING This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).
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Key Words
- ACLF, acute-on-chronic liver failure
- AUROC, area under the receiver operating characteristic curve
- Acute-on-chronic liver failure
- CLIF-C ACLFs, CLIF-C ACLF score
- CLIF-C, chronic liver failure Consortium
- CLIF-OFs, CLIF-organ failure score
- COSSH, Chinese Group on the Study of Severe Hepatitis B
- COSSH-ACLF IIs, COSSH-ACLF II score
- COSSH-ACLFs, COSSH-ACLF score
- EASL, European Association for the Study of the Liver
- HBV, hepatitis B virus
- HE, hepatic encephalopathy
- Hepatitis B virus
- INR, international normalized ratio
- LT, liver transplantation
- Liver transplantation
- MELD-Nas, MELD-sodium score
- MELDs, Model for End-stage Liver Disease score
- PSM, propensity score matching
- Survival benefit
- TB, total bilirubin
- Transplant timing
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Affiliation(s)
- Peng Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Xi Liang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinjin Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Jiaqi Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Jiaojiao Xin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Jing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Dongyan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Yingyan Lu
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Hozeifa Mohamed Hassan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Qian Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Shaorui Hao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Huafen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Tianzhou Wu
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Tan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Heng Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Keke Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Beibei Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Xingping Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Jiaxian Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Lulu He
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Hui Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Wen Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Shiwen Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Bingqi Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Shaoli You
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Shaojie Xin
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yu Chen
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Chinese Group on the Study of Severe Hepatitis B (COSSH)
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
- Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
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24
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Hu M, Liao G, Wei S, Qian Z, Chen H, Xia M, Xie Q, Peng J. Effective Analysis of Antiviral Treatment in Patients with HBeAg-Seropositive Chronic Hepatitis B with ALT < 2 Upper Limits of Normal: A Multi-center Retrospective Cohort Study. Infect Dis Ther 2023; 12:637-647. [PMID: 36633817 PMCID: PMC9925662 DOI: 10.1007/s40121-022-00757-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 12/22/2022] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Although the indications for antiviral therapy for patients with chronic hepatitis B have been gradually expanded in different guidelines, antiviral treatment efficacy remains unclear among HBeAg-seropositive patients with alanine aminotransferase (ALT) < 2 upper limits of normal (ULN). This study aimed to evaluate the efficacy of antiviral therapy for these patients. METHODS In total, 102 treatment-naive patients who were HBeAg seropositive with ALT < 2 ULN and had received nucleotide analogs were included, and their clinical data were retrospectively analyzed. RESULTS After 96-week treatment, 84.3% (n = 86), 26.5% (n = 27) and 20.6% (n = 21) patients achieved virological response, HBeAg seroclearance and HBeAg seroconversion, respectively. Logistic regression analysis revealed that baseline AST (odds ratio [OR] = 1.069, 95% confidence interval [CI] 1.014-1.127, p = 0.014), serum HBV DNA (OR = 0.540, 95% CI 0.309-0.946, p = 0.031) and quantitative HBsAg levels (OR = 0.147, 95% CI 0.036-0.597, p = 0.007) were independent factors for virological response. At baseline, HBsAg < 4.63 log10 IU/ml was identified as a strong predictor for the 96-week virological response, with a concordance rate of 0.902. Moreover, the levels of liver stiffness values (8.30 ± 3.86 vs. 6.17 ± 1.91, p < 0.001) at week 96 had significantly declined compared to baseline. CONCLUSION Nucleotide analog treatment effectively suppressed HBV DNA in patients with HBeAg-seropositive chronic hepatitis B with ALT < 2 × ULN and greatly improved liver fibrosis. The study also found that HBsAg < 4.63 log10 IU/ml was a strong predictor of the virological response.
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Affiliation(s)
- Meixin Hu
- 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
| | - Guichan Liao
- 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
| | - Sufang Wei
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, China
| | - Zhe Qian
- 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
| | - Hongjie 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
| | - Muye Xia
- 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
| | - Qiuli Xie
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, China
| | - Jie Peng
- 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.
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25
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Wu F, Wang Y, Cui D, Tian Y, Lu R, Liu C, Li M, Li Y, Gao N, Jiang Z, Li X, Zhai S, Zhang X, Jia X, Dang S. Short-Term Peg-IFN α-2b Re-Treatment Induced a High Functional Cure Rate in Patients with HBsAg Recurrence after Stopping Peg-IFN α-Based Regimens. J Clin Med 2023; 12:361. [PMID: 36615161 PMCID: PMC9821570 DOI: 10.3390/jcm12010361] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023] Open
Abstract
Little is known about the treatment of patients with hepatitis B surface antigen (HBsAg) recurrence after being clinically cured by peginterferon alpha(peg-IFN-α)-based regimens. This study aimed to investigate the efficacy and safety of peg-IFNα-2b in re-treating patients with HBsAg recurrence after stopping peg-IFN α-based regimens. In this two-center, prospective observational study, 33 patients with HBsAg recurrence after stopping peg-IFN α-based regimens were enrolled and re-treated with an individualized course of peg-IFN α-2b. The hepatitis B virus (HBV) vaccine could be injected immediately after HBsAg clearance, according to patients’ willingness. All patients were monitored and followed-up for 48 weeks after peg-IFN α-2b re-treatment stop. The primary endpoint was HBsAg clearance at the end of follow-up. At baseline, all patients had HBsAg levels of <10 IU/mL and undetectable HBV DNA, with the median HBsAg level of 1.66 (0.56−2.87) IU/mL. After a median of 24 (24−30) weeks of peg-IFN α-2b re-treatment, 87.9% (29/33) of the patients achieved HBsAg clearance again and 66.7% (22/33) of the patients achieved HBsAg seroconversion. At the end of follow-up, the HBsAg clearance and HBsAg seroconversion rates decreased to 78.8% (26/33) and 51.5% (17/33), respectively. Furthermore, 88.9% (16/18) of the patients with HBsAg clearance benefited from receiving the HBV vaccine therapy. Generally, both peg-IFN α-2b and HBV vaccine therapy were well tolerated. A high functional cure rate can be achieved by a short-course of peg-IFN α-2b re-treatment in patients with HBsAg recurrence after stopping peg-IFN α-based regimens. Furthermore, injecting HBV vaccine is beneficial after HBsAg clearance.
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Affiliation(s)
- Fengping Wu
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Yikai Wang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Dandan Cui
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Yan Tian
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Rui Lu
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Chenrui Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Mei Li
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Yaping Li
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Ning Gao
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Zicheng Jiang
- Department of Infectious Diseases, Ankang Central Hospital, Ankang 725000, China
| | - Xuemei Li
- Department of Infectious Diseases, Ankang Central Hospital, Ankang 725000, China
| | - Song Zhai
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Xin Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Xiaoli Jia
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
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26
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Kirino S, Tamaki N, Kurosaki M, Kaneko S, Inada K, Tanaka Y, Ishido S, Yamashita K, Nobusawa T, Matsumoto H, Hayakawa Y, Kakegawa T, Higuchi M, Takaura K, Tanaka S, Maeyashiki C, Yasui Y, Takahashi Y, Tsuchiya K, Nakanishi H, Okamoto R, Izumi N. Alanine aminotransferase levels as therapeutic targets after nucleotide/nucleoside analog therapy in patient with chronic hepatitis B. Hepatol Res 2023; 53:35-42. [PMID: 36117296 DOI: 10.1111/hepr.13839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 01/03/2023]
Abstract
AIM Alanine aminotransferase (ALT) is a criterion for the introduction of nucleotide/nucleoside analog (NA), and ALT levels are decreased by NA treatment. However, the association between post-treatment ALT levels and hepatocellular carcinoma (HCC) risk remains unclear. To fill this gap, we aimed to establish a target value of ALT level during NA treatment. METHODS In total, 413 patients with chronic hepatitis B who received entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. The subsequent development of HCC was examined and a target value of ALT level during NA treatment as a risk marker for HCC was evaluated. RESULTS The median follow-up duration was 5.1 years, during which time 27 patients (8.6%) developed HCC. ALT level at the start of treatment was not associated with HCC development (p = 0.08). When stratified by ALT at 1 year after NA initiation, the cumulative 3- and 5-year rates of HCC for patients with ALT ≥21 IU/L were 11.5% and 18.1%, and those with ALT <21 IU/L was 2.3% and 6.5%, respectively. Patients with ALT <21 IU/L had a significantly lower risk of HCC development compared with patients with ALT ≥21 IU/L (p = 0.002). In multivariable analysis adjusting age, sex, and platelet counts, ALT ≥21 IU/L was an independent risk factor of HCC development with hazard ratio of 4.5 (95% confidence interval: 1.01-20.4). CONCLUSIONS ALT <21 IU/L at 1 year after NA initiation has a lower risk of HCC and could be used as a target value for NA treatment.
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Affiliation(s)
- Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuki Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Ishido
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tsubasa Nobusawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Matsumoto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuya Kakegawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shohei Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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27
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Yardeni D, Chang KM, Ghany MG. Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure. Gastroenterology 2023; 164:42-60.e6. [PMID: 36243037 PMCID: PMC9772068 DOI: 10.1053/j.gastro.2022.10.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/25/2022] [Accepted: 10/04/2022] [Indexed: 02/03/2023]
Abstract
The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Kyong-Mi Chang
- Medical Research, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
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28
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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.
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29
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Yao Y, Zhang J, Li X, Zao X, Cao X, Chen G, Ye Y. Systematic review: Clinical outcomes of discontinuation of oral antivirals in hepatitis B-related liver cirrhosis. Front Public Health 2022; 10:1037527. [PMID: 36407996 PMCID: PMC9670108 DOI: 10.3389/fpubh.2022.1037527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Background Discontinuation of Nucleos(t)ide analogs (NAs) remains one of the most controversial topics in the management of hepatitis B-related liver cirrhosis. However, clinical outcomes after NAs discontinuation have not been studied. Aim The aim of this systematic review is to evaluate existing data on clinical outcomes of NAs withdrawal in chronic hepatitis B (CHB) patients with cirrhosis. Methods A literature search (until May 2022) was performed in order to identify all published studies including hepatitis B-related cirrhotic patients who discontinued NAs in virological remission with off-therapy follow-up >12 months. Results Nineteen studies with 1,287 hepatitis B-related cirrhotic patients were included. Most cirrhotic patients were compensated and achieved complete virological suppression when they stopped the antiviral therapy. The pooled proportions of virological relapse and clinical relapse after NAs discontinuation in cirrhotic patients were 55.23 (95% CI: 40.33-69.67) and 43.56% (95% CI: 26.13-61.85), respectively. HBsAg loss was observed in 56 of 500 (pooled proportion = 13.68%, 95% CI: 5.82-24.18) cirrhotic patients. And the pooled proportions of HCC development, hepatic decompensation and overall mortality were 8.76 (95% CI: 2.25-18.95), 3.63 (95% CI: 1.31-7.03), and 0.85% (95% CI: 0.35-1.57), respectively, after NAs discontinuation in cirrhotic patients. Conclusion In hepatitis B-related compensated cirrhosis, who have achieved complete virological suppression, discontinuation of oral antivirals still carries a high relapse rate, but the incidence of adverse events is generally low and controlled during follow-up of at least 12 months. Of attention is that discontinuation of NAs can achieve a high rate of HBsAg seroclearance. This study may be helpful in the management of NAs in cirrhotic patients. Systematic review registration http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42020170103.
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Affiliation(s)
- Yuhao Yao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- First School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaxin Zhang
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoke Li
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xu Cao
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
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Hu Q, Qi X, Yu Y, Gao Y, Zhang X, Wang Q, Zhang X, Zhuo Y, Li J, Zhang J, Chen L, Huang Y. The efficacy and safety of adding on or switching to peginterferon α-2b in HBeAg-positive chronic hepatitis B patients with long-term entecavir treatment: a multicentre randomised controlled trial. Aliment Pharmacol Ther 2022; 56:1394-1407. [PMID: 36128636 DOI: 10.1111/apt.17222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/27/2022] [Accepted: 09/04/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND & AIMS The strategies of adding on or switching to peginterferon (PEG-IFN) improved the serological response rates in patients with chronic hepatitis B (CHB) who had previously experienced treatment with nucleos(t)ide analogues. However, robust data on which combination strategy is more effective remain lacking. METHODS In this multicentre, parallel, open-label, randomised, controlled trial, patients with HBeAg-positive CHB who were treated with entecavir ≥2 years, and had hepatitis B surface antigen (HBsAg) <3000 IU/ml, HBeAg <200S/CO and HBV DNA <50 IU/ml were randomly assigned in a 1:1:1 ratio to add on PEG-IFN, switch to PEG-IFN or continue entecavir monotherapy for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48. RESULTS A total of 153 patients were randomised into three treatment arms (50 in add-on, 52 in switch-to and 51 in monotherapy). Compared with continuous entecavir monotherapy, both add-on and switch-to strategies achieved higher rates of HBeAg seroconversion (18.0% vs. 2.0%, p = 0.007; 19.2% vs. 2.0%, p = 0.005, respectively), HBeAg loss (24.0% vs. 5.9%, p = 0.010; 23.1% vs. 5.9%, p = 0.013, respectively), HBsAg < 100 IU/ml (30.0% vs. 0%, p < 0.001; 34.6% vs. 0%, p < 0.001, respectively), and higher HBsAg reduction (-0.90 vs. -0.06 log10 IU/ml, p < 0.001; -0.92 vs. -0.06 log10 IU/ml, p < 0.001, respectively) at week 48. The efficacy was comparable between add-on and switch-to arms (p > 0.05). Adverse events were mainly related to PEG-IFN but generally tolerable. CONCLUSION In patients with CHB who achieved virological response with long-term entecavir, both adding on and switching to PEG-IFN are alternative strategies resulting in higher rates of HBeAg seroconversion and HBsAg reduction than continuous entecavir. CLINICAL TRIALS REGISTRATION Chinese Clinical Trial Registry (www.chictr.org.cn, identifier: ChiCTR-IPR-17012055).
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Affiliation(s)
- Qiankun Hu
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xun Qi
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yiqi Yu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yueqiu Gao
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianqian Wang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yunhui Zhuo
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Li
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Liang Chen
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Liver Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.,Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
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31
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Xu JH, Wang S, Zhang DZ, Yu YY, Si CW, Zeng Z, Xu ZN, Li J, Mao Q, Tang H, Sheng JF, Chen XY, Ning Q, Shi GF, Xie Q, Zhang XQ, Dai J. One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C. World J Clin Cases 2022; 10:10085-10096. [PMID: 36246814 PMCID: PMC9561570 DOI: 10.12998/wjcc.v10.i28.10085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/12/2022] [Accepted: 08/24/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.
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Affiliation(s)
- Jing-Hang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Sa Wang
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Da-Zhi Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital with Chongqing Medical University, Chongqing 400010, China
| | - Yan-Yan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Chong-Wen Si
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Zheng Zeng
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Zhong-Nan Xu
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Qing Mao
- Department of Infectious Diseases, Southwest China Hospital, Chongqing 400038, China
| | - Hong Tang
- Department of Infectious Diseases, West China Hospital, Chengdu 610041, Sichuan Province, China
| | - Ji-Fang Sheng
- Department of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou 310010, Zhejiang Province, China
| | - Xin-Yue Chen
- Department of International Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qin Ning
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Guang-Feng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai 200025, China
| | - Xi-Quan Zhang
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
| | - Jun Dai
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
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Mutimer D, Elsharkawy A, Hathorn E, Arunkumar S. Hepatitis B e antigen and e antibody in a multi-ethnic cohort of adult chronic hepatitis B virus patients followed at a single liver unit for a period of 20 years. J Viral Hepat 2022; 29:879-889. [PMID: 35792009 DOI: 10.1111/jvh.13731] [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: 06/03/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 12/09/2022]
Abstract
Hepatitis B virus e antigen (HBeAg) loss and the appearance of antibodies to HBeAg (anti-HBe) are favourable events in the history of chronic hepatitis B virus (CHB) infection. Most CHB patients have the HBeAg/anti-HBe profiles +/- or -/+, and little is published on the derivation or fate of the +/+ and -/- profiles. We have used electronically accessible patient data to study the HBeAg and anti-HBe profiles of a multi-ethnic cohort of adult HBV patients seen at a single centre over a period of more than 20 years. 3594 HBsAg-positive patients were identified and patients with viral coinfection or acute HBV infection were excluded. Cross-sectional and longitudinal analyses of HBeAg/anti-HBe status were undertaken. Compared with White or Black patients, Chinese and Asian patients are more likely to be HBeAg positive during child-bearing years. Patients with +/+ profile are likely to undergo HBeAg loss and seroconversion during relatively short follow-up. Chinese patients have a relatively increased rate of seroconversion. For HBeAg-positive patients, the risk of seroconversion diminishes with advancing age. Despite HBeAg loss, seroconversion is seldom observed after age 60 years. The proportion of HBV patients with -/- increases with age, and most acquire this profile by HBeAg loss but without antecedent seroconversion. -/- patients can lose HBsAg and develop anti-HBs. It was not possible to demonstrate a favourable impact of antiviral treatment on the rate of HBeAg seroconversion.
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Affiliation(s)
- David Mutimer
- Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Ahmed Elsharkawy
- Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Emma Hathorn
- Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Selvi Arunkumar
- Health Informatics, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, UK
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Xu J, Fan Y, Yu Y, Si C, Zeng Z, Xu Z, Li J, Mao Q, Zhang D, Tang H, Sheng J, Chen X, Ning Q, Shi G, Xie Q, Zhang X, Dai J. 240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C. J Viral Hepat 2022; 29:862-867. [PMID: 35737855 PMCID: PMC9545224 DOI: 10.1111/jvh.13724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 04/25/2022] [Indexed: 02/05/2023]
Abstract
This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.
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Affiliation(s)
- Jing‐Hang Xu
- Department of Infectious Diseases, Center for Liver DiseasesPeking University First HospitalBeijingChina
| | - Ya‐Nan Fan
- Department of Infectious Diseases, Center for Liver DiseasesPeking University First HospitalBeijingChina
| | - Yan‐Yan Yu
- Department of Infectious Diseases, Center for Liver DiseasesPeking University First HospitalBeijingChina
| | - Chong‐Wen Si
- Department of Infectious Diseases, Center for Liver DiseasesPeking University First HospitalBeijingChina
| | - Zheng Zeng
- Department of Infectious Diseases, Center for Liver DiseasesPeking University First HospitalBeijingChina
| | - Zhong‐Nan Xu
- Jiangsu Chia‐tai Tianqing Pharmaceutical Co, LtdNanjingChina
| | - Jun Li
- Department of Infectious DiseasesThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Qing Mao
- Department of Infectious DiseasesSouthwest China HospitalChongqingChina
| | - Da‐Zhi Zhang
- Department of Infectious DiseasesThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Hong Tang
- Department of Infectious DiseasesWest China HospitalChengduChina
| | - Ji‐Fang Sheng
- Department of Infectious DiseasesThe First Affiliated Hospital of Zhejiang UniversityHangzhouChina
| | - Xin‐Yue Chen
- Department of International Medicine, Beijing Youan HospitalCapital Medical UniversityBeijingChina
| | - Qin Ning
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Guang‐Feng Shi
- Department of Infectious Diseases, Huashan HospitalFudan UniversityShanghaiChina
| | - Qing Xie
- Department of Infectious Diseases, Ruijin HospitalJiaotong University School of MedicineShanghaiChina
| | - Xi‐Quan Zhang
- Jiangsu Chia‐tai Tianqing Pharmaceutical Co, LtdNanjingChina
| | - Jun Dai
- Jiangsu Chia‐tai Tianqing Pharmaceutical Co, LtdNanjingChina
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Woo HY, Heo J, Tak WY, Lee HJ, Chung WJ, Park JG, Park SY, Park YJ, Lee YR, Hwang JS, Kweon YO. Effect of switching from nucleos(t)ide maintenance therapy to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomized trial. PLoS One 2022; 17:e0270716. [PMID: 35867702 PMCID: PMC9307167 DOI: 10.1371/journal.pone.0270716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/14/2022] [Indexed: 11/22/2022] Open
Abstract
AIMS Induction of a durable viral response is difficult to achieve in patients with chronic hepatitis B (CHB), even from long-term use of a nucleos(t)ide analogue (NA). This study investigated whether switching to peginterferon (PegIFN) alfa-2a after long-term NA therapy induced a durable viral response. METHODS Patients with hepatitis B e antigen (HBeAg)-positive CHB who received any NA for at least 72 weeks and had a low level of HBV DNA (≤100 IU/mL) were randomized (1:1) to receive PegIFN alfa-2a (180 μg/week) or NA for 48 weeks. The primary endpoint was change in the hepatitis B surface antigen (HBsAg) titer during antiviral therapy. RESULTS We randomized 149 CHB patients to the two groups. Compared to baseline, the HBsAg levels in both groups were not lower at week 12, but were lower after 24, 36, and 48 weeks (all p<0.001). The maximal HBsAg decline in the PegIFN alfa-2a group was at week 36 (0.50±0.88 log10 IU/mL), and this decline was smaller in the NA group (0.08±0.46 log10 IU/mL). The percentage of patients with HBeAg seroconversion at week 48 was also greater in the PegIFN alfa-2a group (15/75 [20.0%] vs. 5/74 [6.8%], p = 0.018). Multivariable analysis indicated the PegIFN alfa-2a group had a greater change in HBeAg seroconversion at week 48 (p = 0.027). Patients had relatively good tolerance to PegIFN alfa-2a therapy. CONCLUSIONS CHB patients who switched to PegIFN alfa-2a for 48 weeks had a significantly lower HBsAg titer and increased HBeAg seroconversion relative to those who remained on NA therapy. TRIAL REGISTRATION (ClinicalTrials.gov; NCT01769833).
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Won Young Tak
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Woo Jin Chung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Jung Gil Park
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Young Joo Park
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Yu Rim Lee
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Young Oh Kweon
- Department of Internal Medicine, College of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
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Fung S, Choi HSJ, Gehring A, Janssen HLA. Getting to HBV cure: The promising paths forward. Hepatology 2022; 76:233-250. [PMID: 34990029 DOI: 10.1002/hep.32314] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV-DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.
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Affiliation(s)
- Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Adam Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
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Broquetas T, Carrión JA. Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepat Med 2022; 14:87-100. [PMID: 35936810 PMCID: PMC9346298 DOI: 10.2147/hmer.s291976] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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Loggi E, Gitto S, Gabrielli F, Franchi E, Seferi H, Cursaro C, Andreone P. Virological Treatment Monitoring for Chronic Hepatitis B. Viruses 2022; 14:1376. [PMID: 35891357 PMCID: PMC9319170 DOI: 10.3390/v14071376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022] Open
Abstract
More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility.
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Affiliation(s)
- Elisabetta Loggi
- Hepatology Unit, Department of Medical & Surgical Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
| | - Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Elena Franchi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
| | - Hajrie Seferi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy; (F.G.); (E.F.); (H.S.)
| | - Carmela Cursaro
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy;
| | - Pietro Andreone
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy;
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Medicina Interna Metabolico-Nutrizionale, Ospedale Civile di Baggiovara, Via Pietro Giardini 1355, 41126 Modena, Italy
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Ward AS, Hsiung CH, Kesterson DG, Kamath VG, McKee EE. Entecavir competitively inhibits deoxyguanosine and deoxyadenosine phosphorylation in isolated mitochondria and the perfused rat heart. J Biol Chem 2022; 298:101876. [PMID: 35358513 PMCID: PMC9097457 DOI: 10.1016/j.jbc.2022.101876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 10/26/2022] Open
Abstract
Deoxyguanosine kinase (dGK) is reported responsible for the phosphorylation of deoxyadenosine (dA) and deoxyguanosine (dG) in the mitochondrial purine salvage pathway. Antiviral nucleoside analogs known as nucleoside reverse transcriptase inhibitors (NRTIs) must be phosphorylated by host enzymes for the analog to become active. We address the possibility that NRTI purine analogs may be competitive inhibitors of dGK. From a group of such analogs, we demonstrate that entecavir (ETV) competitively inhibited the phosphorylation of dG and dA in rat mitochondria. Mitochondria from the brain, heart, kidney, and liver showed a marked preference for phosphorylation of dG over dA (10-30-fold) and ETV over dA (2.5-4-fold). We found that ETV inhibited the phosphorylation of dG with an IC50 of 15.3 ± 2.2 μM and that ETV and dG were both potent inhibitors of dA phosphorylation with IC50s of 0.034 ± 0.007 and 0.028 ± 0.006 μM, respectively. In addition, the phosphorylation of dG and ETV followed Michaelis-Menten kinetics and each competitively inhibited the phosphorylation of the other. We observed that the kinetics of dA phosphorylation were strikingly different from those of dG phosphorylation, with an exponentially lower affinity for dGK and no effect of dA on dG or ETV phosphorylation. Finally, in an isolated heart perfusion model, we demonstrated that dG, dA, and ETV were phosphorylated and dG phosphorylation was inhibited by ETV. Taken together, these data demonstrate that dGK is inhibited by ETV and that the primary role of dGK is in the phosphorylation of dG rather than dA.
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Affiliation(s)
- Avery S Ward
- Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA
| | - Chia-Heng Hsiung
- Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA; School of Science, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang Province, China
| | - Daniel G Kesterson
- Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA; Department of Health Management and Policy, University of Michigan School of Public Health, University of Michigan, Ann Arbor, Michigan, USA
| | - Vasudeva G Kamath
- Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA; Department of Basic Medical Sciences, Touro College of Osteopathic Medicine, Middletown, New York, USA
| | - Edward E McKee
- Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
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A novel model based on qAnti-HBc and conventional biomarkers for identifying significant liver injury among CHB patients with ALT ≤ ULN. Antiviral Res 2022; 202:105315. [PMID: 35398103 DOI: 10.1016/j.antiviral.2022.105315] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 02/09/2022] [Accepted: 04/03/2022] [Indexed: 11/19/2022]
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40
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Shi Z, Zheng H, Han M, Hu J, Hu Y, Li X, Zhu W, He X, Deng H, Long Q, Huang A. Durability of Hepatitis B surface antigen seroclearance in patients experienced nucleoside analogs or interferon monotherapy: A real-world data from Electronic Health Record. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Takaura K, Kurosaki M, Inada K, Kirino S, Yamashita K, Muto T, Osawa L, Sekiguchi S, Hayakawa Y, Higuchi M, Kaneko S, Maeyashiki C, Tamaki N, Yasui Y, Itakura J, Tsuchiya K, Nakanishi H, Takahashi Y, Izumi N. The impact of background liver disease on the long-term prognosis of very-early-stage HCC after ablation therapy. PLoS One 2022; 17:e0264075. [PMID: 35196341 PMCID: PMC8865683 DOI: 10.1371/journal.pone.0264075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 02/02/2022] [Indexed: 12/24/2022] Open
Abstract
Background and aim The long-term prognosis of hepatocellular carcinoma (HCC) treated at a very-early-stage (the Barcelona Clinical Liver Cancer (BCLC) classification stage 0) was unclear, especially in terms of background liver disease. Methods This single-center, retrospective study included 302 patients with BCLC stage 0 HCC treated with radiofrequency ablation (RFA) and followed for at least six months. We examined the impact of background liver disease on overall survival and recurrence. Results The median age was 72 (range; 36–91) years; the median tumor diameter was 15 (range; 8–20) mm. The etiologies of background liver disease were hepatitis B virus infection (HBV) in 24 cases, hepatitis C virus infection (HCV) in 195 cases, and non-viral (NBNC) in 83 cases. Among the patients with HCV, 63 had achieved sustained virological response (SVR) by antiviral therapy (HCV SVR) before developing HCC (n = 37) or after HCC treatment (n = 26), and 132 had active HCV infection (HCV non-SVR). The median overall survival was 85 (95% CI; 72–98) months, and the median recurrence-free survival was 26 (95% CI; 20–30) months. Active infection with hepatitis C virus negatively contributed to overall survival (HR 2.91, 95% CI 1.31–3.60, p = 0.003) and recurrence-free survival (HR 1.47, 95% CI 1.06–2.05, p = 0.011). Conclusions The prognosis of RFA treatment for very early-stage HCC was favorable. Achieving SVR in hepatitis C was important for further prognosis improvement.
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Affiliation(s)
- Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kouji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tomohiro Muto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shuhei Sekiguchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- Division of Medicine, NAFLD Research Center, University of California, San Diego, La Jolla, California, United States of America
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- * E-mail:
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Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses 2022; 14:v14020434. [PMID: 35216027 PMCID: PMC8877417 DOI: 10.3390/v14020434] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.
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Abstract
Chronic hepatitis B virus (HBV) infection remains a global health burden. Timely and effective antiviral therapy is beneficial for patients with HBV infection. With existing antiviral drugs, including nucleos(t)ide analogs and interferon-alfa, patients can achieve viral suppression with improved prognosis. However, the rate of hepatitis B surface antigen loss is low. To achieve a functional cure and even complete cure in chronic hepatitis B patients, new antivirals need to be developed. In this review, we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.
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Cheng K, Chen Y, Wang X, Xu M, Liao W, Duan X, Zhao X, Sun Y, Duan Z, Wang L. Entecavir combined with interferon-α Is superior to entecavir monotherapy in reducing hepatic and extrahepatic cancer in patients with chronic hepatitis B. Cancer 2022; 128:558-569. [PMID: 34623636 DOI: 10.1002/cncr.33949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND The objective of this study was to assess whether entecavir (ETV) in combination with interferon-α (IFN-α) could reduce hepatocellular cancer (HCC) and extrahepatic cancers (EHCs) in patients with chronic hepatitis B (CHB). METHODS The cohort consisted of 4194 patients with CHB treated with ETV combined with IFN-α or ETV monotherapy at a tertiary hospital in Beijing, China, from January 2009 to December 2017. The risks, hazard ratios (HRs), and 95% confidence intervals (CIs) of HCC and EHCs were compared in the 2 groups. RESULTS In a multivariate Cox regression analysis, a significantly lower risk of HCC (HR, 0.6; 95% CI, 0.3-0.9; P = .0310) and a marginally significantly lower risk of EHCs (HR, 0.2; 95% CI, 0.02-1.3; P = .0854) were observed in the group receiving ETV combined with IFN-α in comparison with the ETV monotherapy group. The annual virological response rates were significantly higher in the combination therapy group versus the monotherapy group (33.8% vs 21.2%; P < .0001), but the hepatitis B surface antigen (HBsAg) seroclearance rates were not (1.2% vs 0.9%; P = .8537). The HRs were consistent with propensity score-based matching, inverse probability weighting adjustments, and adjustments for virological response and HBsAg seroclearance. CONCLUSIONS ETV combined with IFN-α therapy is superior to ETV monotherapy in reducing the risk of HCC and EHCs for patients with CHB. People who can tolerate and benefit from IFN-α therapy could consider combination therapy.
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Affiliation(s)
- Kailiang Cheng
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Xiaomo Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Manman Xu
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Wei Liao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | | | - Xinyu Zhao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yuanyuan Sun
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhongping Duan
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
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Nkongolo S, Hollnberger J, Urban S. [Bulevirtide as the first specific agent against hepatitis D virus infections-mechanism and clinical effect]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65:254-263. [PMID: 35028672 PMCID: PMC8813823 DOI: 10.1007/s00103-022-03486-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/22/2021] [Indexed: 12/19/2022]
Abstract
Die Blockade des Zelleintritts von Krankheitserregern ist ein geeigneter Ansatz, um Neuinfektionen zu verhindern. Der therapeutische Einsatz von Eintrittsinhibitoren bei chronisch infizierten Patienten war jedoch bisher nur begrenzt erfolgreich. Zur Behandlung von chronischen Hepatitis-D-Virus-(HDV-)Infektionen wurde im Juli 2020 mit Bulevirtide (BLV) ein vielversprechender Wirkstoff bedingt zugelassen, der auf diesem Wirkprinzip beruht. Zuvor hatten für HDV keine gezielte Medikation zur Verfügung gestanden und die Behandlung beruhte auf dem Off-Label-Einsatz von Interferon-Alpha/Peginterferon-Alpha (IFNα/Peg-IFNα). In diesem Beitrag wird ein Überblick über die Grundlagen des Wirkmechanismus von BLV gegeben und bisher vorliegende klinische Daten werden zusammengefasst. Eine HDV-Infektion manifestiert sich als Ko- oder Superinfektion bei Hepatitis-B-Virus-(HBV-)Infektionen und betrifft 4,5–15 % der HBV-Patienten weltweit. HDV nutzt die Hüllproteine von HBV zur Verbreitung. BLV wirkt, indem es den HBV/HDV-Rezeptor natriumtaurocholat-co-transportierendes Polypeptid (NTCP) blockiert und so den Eintritt von HBV/HDV in Hepatozyten verhindert. BLV senkt die HDV-Serum-RNA-Spiegel und führt bei HBV/HDV-infizierten Personen zur Normalisierung der Alanin-Aminotransferase-(ALT-)Werte. Es hat ein ausgezeichnetes Sicherheitsprofil, selbst wenn es über 48 Wochen in hohen Dosen (10 mg täglich) verabreicht wird. In Kombination mit Peg-IFNα zeigt BLV synergistische Effekte auf die Senkung der HDV-RNA im Serum, aber auch auf die Hepatitis-B-Oberflächenantigen-(HBsAg‑)Spiegel. Dies führte bei einer Untergruppe von Patienten zu einer funktionellen Heilung, wenn 2 mg BLV plus Peg-IFNα verabreicht wurden. Der Mechanismus dieser wahrscheinlich immunvermittelten Eliminierung wird in Folgestudien untersucht.
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Affiliation(s)
- Shirin Nkongolo
- Molekulare Virologie, Translationale Virologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Deutschland.,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Heidelberg, Deutschland.,Toronto Centre for Liver Disease, University Health Network, Toronto, Kanada
| | - Julius Hollnberger
- Molekulare Virologie, Translationale Virologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Deutschland.,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Heidelberg, Deutschland
| | - Stephan Urban
- Molekulare Virologie, Translationale Virologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Deutschland. .,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Heidelberg, Deutschland.
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Kim SW, Yoon JS, Lee M, Cho Y. Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus. Clin Mol Hepatol 2022; 28:17-30. [PMID: 34281294 PMCID: PMC8755466 DOI: 10.3350/cmh.2021.0093] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/05/2021] [Accepted: 07/18/2021] [Indexed: 11/09/2022] Open
Abstract
Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.
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Affiliation(s)
- Sun Woong Kim
- Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea
| | - Jun Sik Yoon
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Minjong Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
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Zhang Q, Peng H, Liu X, Wang H, Du J, Luo X, Ren H, Hu P. Chronic Hepatitis B Infection with Low Level Viremia Correlates with the Progression of the Liver Disease. J Clin Transl Hepatol 2021; 9:850-859. [PMID: 34966648 PMCID: PMC8666364 DOI: 10.14218/jcth.2021.00046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/21/2021] [Accepted: 04/18/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND AIMS Currently, insufficient clinical data are available to address whether low-level viremia (LLV) observed during antiviral treatment will adversely affect the clinical outcome or whether treatment strategies should be altered if LLV occurs. This study compared the clinical outcomes of patients with a maintained virological response (MVR) and patients who experienced LLV and their treatment strategies. METHODS A retrospective cohort of 674 patients with chronic hepatitis B virus (HBV) infection who received antiviral treatment for more than 12 months was analyzed for the development of end-stage liver disease and treatment strategies during the follow-up period. End-stage liver disease included decompensated liver cirrhosis and hepatocellular carcinoma (HCC). RESULTS During a median 42-month follow-up, end-stage liver disease developed more frequently in patients who experienced LLV than in those who experienced MVR (7.73% and 15.85% vs. 0.77% and 5.52% at 5 and 10 years, respectively; p=0.000). The trend was consistent after propensity score matching. In the high-risk group of four HCC risk models, LLV patients had a higher risk of HCC development (p<0.05). By Cox proportional hazard model analysis, LLV was an independent risk factor for end-stage liver disease and HCC (hazard ratio [HR]=6.280, confidence interval [CI]=2.081-18.951, p=0.001; HR=5.108, CI=1.392-18.737, respectively; p=0.014). Patients achieved a lower rate of end-stage liver disease by adjusting treatment compared to continuing the original treatment once LLV occurred (p<0.05). CONCLUSIONS LLV is an independent risk factor for end-stage liver disease and HCC, and treatment adjustments can be considered.
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Affiliation(s)
- Qian Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Peng
- Department of Infectious Diseases, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| | - Xiaoqing Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huimin Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jinjie Du
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xinhua Luo
- Department of Infectious Diseases, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| | - Hong Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Correspondence to: Peng Hu and Hong Ren, Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China. ORCID: http://orcid.org/0000-0001-8481-0841 (PH), https://orcid.org/0000-0002-4557-0918 (HR). Tel: +86-23-6288-7083, Fax: +86-23-6370-3790, E-mail: (PH), (PH), (HR)
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Correspondence to: Peng Hu and Hong Ren, Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China. ORCID: http://orcid.org/0000-0001-8481-0841 (PH), https://orcid.org/0000-0002-4557-0918 (HR). Tel: +86-23-6288-7083, Fax: +86-23-6370-3790, E-mail: (PH), (PH), (HR)
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Xiao LL, Wu XX, Chen JJ, Yan D, Shi DY, Huang JR, Xu XW, Li LJ. Progress in hepatitis B virus-related acute-on-chronic liver failure treatment in China: A large, multicenter, retrospective cohort study using a propensity score matching analysis. Hepatobiliary Pancreat Dis Int 2021; 20:535-541. [PMID: 34303609 DOI: 10.1016/j.hbpd.2021.05.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 05/25/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality. However, the treatment progression for HBV-ACLF in China in the past decade has not been well characterized. The present study aimed to determine whether the HBV-ACLF treatment has significantly improved during the past decade. METHODS This study retrospectively compared short-term (28/56 days) survival rates of two different nationwide cohorts (cohort I: 2008-2011 and cohort II: 2012-2015). Eligible HBV-ACLF patients were enrolled retrospectively. Patients in the cohorts I and II were assigned either to the standard medical therapy (SMT) group (cohort I-SMT, cohort II-SMT) or artificial liver support system (ALSS) group (cohort I-ALSS, cohort II-ALSS). Propensity score matching analysis was conducted to eliminate baseline differences, and multivariate logistic regression analysis was used to explore the independent factors for 28-day survival. RESULTS Short-term (28/56 days) survival rates were significantly higher in the ALSS group than those in the SMT group (P < 0.05) and were higher in the cohort II than those in the cohort I (P < 0.001). After propensity score matching, short-term (28/56 days) survival rates were higher in the cohort II than those in the cohort I for both SMT (60.7% vs. 53.0%, 50.0% vs. 39.8%, P < 0.05) and ALSS (66.1% vs. 56.5%, 53.0% vs. 44.4%, P < 0.05) treatments. The 28-day survival rate was higher in patients treated with nucleos(t)ide analogs than in patients without such treatments (P = 0.046). Multivariate logistic regression analysis revealed that ALSS (OR = 0.962, 95% CI: 0.951-0.973, P = 0.038), nucleos(t)ide analogs (OR = 0.927, 95% CI: 0.871-0.983, P = 0.046), old age (OR = 1.028, 95% CI: 1.015-1.041, P < 0.001), total bilirubin (OR = 1.002, 95% CI: 1.001-1.003, P = 0.004), INR (OR = 1.569, 95% CI: 1.044-2.358, P < 0.001), COSSH-ACLF grade (OR = 2.683, 95% CI: 1.792-4.017, P < 0.001), and albumin (OR = 0.952, 95% CI: 0.924-0.982, P = 0.002) were independent factors for 28-day mortality. CONCLUSIONS The treatment for patients with HBV-ACLF has improved in the past decade.
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Affiliation(s)
- Lan-Lan Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Xiao-Xin Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Jia-Jia Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Dong-Yan Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Jian-Rong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
| | - Xiao-Wei Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
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Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ. Antiviral Res 2021; 197:105220. [PMID: 34848218 DOI: 10.1016/j.antiviral.2021.105220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/16/2021] [Accepted: 11/25/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT. METHODS In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication. RESULTS 33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers. CONCLUSIONS In NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.
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Yu JH, Cho SG, Jin YJ, Lee JW. The best predictive model for hepatocellular carcinoma in patients with chronic hepatitis B infection. Clin Mol Hepatol 2021; 28:351-361. [PMID: 34823308 PMCID: PMC9293610 DOI: 10.3350/cmh.2021.0281] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/25/2021] [Indexed: 11/06/2022] Open
Abstract
Chronic hepatitis B (CHB) seriously threatens human health. About 820,000 deaths annually are due to related complications such as hepatitis B and hepatocellular carcinoma (HCC). Recently, the use of oral antiviral agents has significantly improved the prognosis of patients with CHB infection and reduced the risk of HCC. However, hepatitis B virus still remains a major factor in the development of HCC, raising many concerns. Therefore, numerous studies have been conducted to assess the risk of HCC in patients with CHB infection and many models have been proposed to predict the risk of developing HCC. However, as each study has different models for predicting HCC development that can be applied depending on the use of antiviral agents or the type of antiviral agents, it is necessary to properly understand characteristics of each model when using it for the evaluation of HCC in patients with CHB infection. In addition, because different variables such as host factor, viral activity, and cirrhosis are used to evaluate the risk of HCC development, it is necessary to assess the risk by carefully verifying which variables are used. Recently, studies have also evaluated the risk of HCC using risk prediction models through transient elastography and artificial intelligence (AI) system. These HCC risk predication models are also noteworthy. In this review, we aimed to compare HCC risk prediction models in patients with CHB infection reported to date to confirm variables used and specificity between each model to determine an appropriate HCC risk prediction method.
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Affiliation(s)
- Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, South Korea
| | - Soon Gu Cho
- Department of Radiology, Inha University Hospital and School of Medicine, Incheon, South Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, South Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, South Korea
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