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Cornberg M, Sandmann L, Jaroszewicz J, Kennedy P, Lampertico P, Lemoine M, Lens S, Testoni B, Lai-Hung Wong G, Russo FP. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2025:S0168-8278(25)00174-6. [PMID: 40348683 DOI: 10.1016/j.jhep.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.
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Maung ST, Decharatanachart P, Treeprasertsuk S, Chaiteerakij R. Risk Factors for Development of Cirrhosis in Chronic Viral Hepatitis B Patients Who Had Persistent Viral Suppression With Antiviral Therapy. J Clin Exp Hepatol 2024; 14:101388. [PMID: 38523735 PMCID: PMC10956063 DOI: 10.1016/j.jceh.2024.101388] [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: 09/13/2023] [Accepted: 02/24/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND AND AIMS Chronic viral hepatitis B (CHB)-infected patients occasionally develop cirrhosis despite having persistent viral suppression with antiviral therapy. We aimed to identify risk factors for developing cirrhosis in hepatitis B virus (HBV)-suppressed patients. METHODS We conducted a case-control study involving 120 noncirrhotic CHB-infected patients achieving viral suppression with antiviral treatment, with 40 cases developing cirrhosis and 80 age-, sex-, and Fibrosis-4 (FIB-4)-matched controls. Clinical and laboratory data at viral suppression, including body mass index (BMI), comorbidities, pretreatment HBV viral load, HBe antigen status, hepatitis C virus (HCV) and HIV coinfections, liver chemistries, and AST to Platelets Ratio Index (APRI) values, were retrospectively abstracted. Risk factors for cirrhosis post-HBV suppression were identified using Cox proportional hazard analysis. RESULTS Case and control groups had similar ages (51.4 ± 9.9 vs. 51.4 ± 10.2 years), proportions of males (80% vs. 80%), and FIB-4 values (1.32 vs. 1.31). The cirrhosis group showed significantly higher BMI (25.1 vs. 22.7, P = 0.01) and more diabetes prevalence (50.0% vs. 26.3%, P = 0.01), while other comorbidities and laboratory parameters were comparable (P > 0.05). By univariate analysis, BMI >23 kg/m2, diabetes, and APRI >0.7 were significantly associated with cirrhosis, with hazard ratios (HRs) (95%CI) of 2.99 (1.46-6.13), 2.31 (1.23-4.36), and 2.71 (1.05-6.99), P = 0.003, 0.010, and 0.039, respectively. In multivariate analyses adjusted for APRI, BMI>23 kg/m2 remained significantly associated with cirrhosis (aHR: 2.76, P = 0.006), while diabetes showed borderline significance (aHR: 1.99, P = 0.072). CONCLUSIONS In HBV-infected patients achieving viral suppression with therapy, a BMI >23 kg/m2 increases the risk of cirrhosis. Therefore, a comprehensive approach addressing metabolic factors is imperative for preventing disease progression in HBV-infected patients.
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Affiliation(s)
- Soe T. Maung
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Ma Har Myaing Hospital, Yangon, Myanmar
| | | | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Du T, Yu B, Luo W. Liver cirrhosis reversal and recompensation: Existing evidence and future prospects. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:320-326. [DOI: 10.11569/wcjd.v32.i5.320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
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Luo J, Yuan M, Li S, Chen L, Zhou M, Li H, Bai X, Zhang Z, Zeng W, Sun X, Zhang Q, Chen Y, Zhou L. Dynamic evaluation of liver fibrosis to assess hepatocellular carcinoma risk in patients with chronic hepatitis B receiving nucleoside analogs treatment. Rev Inst Med Trop Sao Paulo 2024; 66:e27. [PMID: 38747848 PMCID: PMC11095248 DOI: 10.1590/s1678-9946202466027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/28/2024] [Indexed: 05/19/2024] Open
Abstract
Despite good hepatitis B virus (HBV) inhibition by nucleoside analogs (NAs), cases of hepatocellular carcinoma (HCC) still occur. This study proposed a non-invasive predictive model to assess HCC risk in patients with chronic hepatitis B (CHB) receiving NAs treatment. Data were obtained from a hospital-based retrospective cohort registered on the Platform of Medical Data Science Academy of Chongqing Medical University, from 2013 to 2019. A total of 501 patients under NAs treatment had their FIB-4 index updated semiannually by recalculation based on laboratory values. Patients were divided into three groups based on FIB-4 index values: < 1.45, 1.45-3.25, and ≥ 3.25. Subsequently, HCC incidence was reassessed every six months using Kaplan-Meier curves based on the updated FIB-4 index. The median follow-up time of CHB patients after receiving NAs treatment was 2.5 years. HCC incidences with FIB-4 index < 1.45, 1.45-3.25, and ≥ 3.25 were 1.18%, 1.32%, and 9.09%, respectively. Dynamic assessment showed that the percentage of patients with FIB-4 index < 1.45 significantly increased semiannually (P < 0.001), and of patients with FIB-4 index ≥ 3.25 significantly decreased (P < 0.001). HCC incidence was the highest among patients with FIB-4 index ≥ 3.25. The FIB-4 index effectively predicted HCC incidence, and its dynamic assessment could be used for regular surveillance to implement early intervention and reduce HCC risk.
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Affiliation(s)
- Jia Luo
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Ming Yuan
- Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Shan Li
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Lijuan Chen
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Mingsha Zhou
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Hailan Li
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
| | - Xiuyuan Bai
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Zhiyu Zhang
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Weiqi Zeng
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Xueyi Sun
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Qiongfang Zhang
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Yi Chen
- Chongqing Medical University, School of Public Health, Chongqing, China
| | - Li Zhou
- Chongqing Medical University, School of Public Health, Department of Epidemiology, Chongqing, China
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Chang X, Lv C, Wang B, Wang J, Song Z, An L, Chen S, Chen Y, Shang Q, Yu Z, Tan L, Li Q, Liu H, Jiang L, Xiao G, Chen L, Lu W, Hu X, Dong Z, Chen Y, Sun Y, Wang X, Li Z, Chen D, You H, Jia J, Yang Y. The utility of P-I-R classification in predicting the on-treatment histological and clinical outcomes of patients with hepatitis B and advanced liver fibrosis. Hepatology 2024; 79:425-437. [PMID: 37611260 PMCID: PMC10789381 DOI: 10.1097/hep.0000000000000563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 07/01/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND AND AIMS The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. APPROACH AND RESULTS In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases ( p <0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55-56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). CONCLUSIONS The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.
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Affiliation(s)
- Xiujuan Chang
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Caihong Lv
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Bingqiong Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jing Wang
- Department of Hepatobiliary Disease, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
| | - Zheng Song
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Linjing An
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shuyan Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yongping Chen
- Department of Infectious and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Qinghua Shang
- Department of Liver Diseases, the 960th Hospital of Chinese PLA Joint Logistics Support Force, Jinan, Shandong Province, China
| | - Zujiang Yu
- Department of Infectious Disease, the First Affiliated Hospital of Zhengzhou, University, Zhengzhou, Henan Province, China
| | - Lin Tan
- Department of Liver Disease, Fuyang 2nd People’s Hospital, Fuyang, Anhui Province, China
| | - Qin Li
- Fuzhou Infectious Diseases Hospital, Fuzhou, Fujian Province, China
| | - Huabao Liu
- Traditional Chinese Medicine Hospital of Chongqing, Chongqing, China
| | - Li Jiang
- Department of Infectious Diseases, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Guangming Xiao
- Guangzhou 8th People's Hospital, Guangzhou, Guangdong Province, China
| | - Liang Chen
- Department of Hepatic Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Wei Lu
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Xiaoyu Hu
- National Integrative Medicine Clinical Base for Infectious Diseases and Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Zheng Dong
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yan Chen
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xiaodong Wang
- Department of Infectious and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zhiqin Li
- Department of Infectious Disease, the First Affiliated Hospital of Zhengzhou, University, Zhengzhou, Henan Province, China
| | - Da Chen
- Fuzhou Infectious Diseases Hospital, Fuzhou, Fujian Province, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yongping Yang
- Department of Liver Disease, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
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Huang YH, Shen CW, Chen CY, Bair MJ. Comparative effectiveness of tenofovir versus entecavir in patients with hepatitis B virus-related cirrhosis in Taiwan: a retrospective cohort study. Front Pharmacol 2023; 14:1301120. [PMID: 38174221 PMCID: PMC10763146 DOI: 10.3389/fphar.2023.1301120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Background: Tenofovir and entecavir demonstrated substantial effectiveness in the reversion of fibrosis and reversed cirrhosis in patients with hepatitis B virus (HBV)-related cirrhosis. However, there has not been a definitive conclusion regarding the association between entecavir and tenofovir on the risk of cirrhosis-related complications. Therefore, this study aimed to investigate the comparative effectiveness between tenofovir and entecavir in HBV-related cirrhosis patients. Methods: This was a retrospective study using Taiwan's Health Insurance Research Database. We enrolled newly diagnosed HBV-related cirrhosis patients who initiated entecavir and tenofovir between 2011 and 2019. Treatment groups were determined by the initial HBV antiviral medication prescribed. The primary composite outcome was the development of hepatocellular carcinoma (HCC), death from any causes, and liver transplantation. The secondary outcomes included all the individual components of the primary outcome. The incidence rate was calculated for each outcome for both treatment groups using the Fine-Gray subdistribution hazard models. Propensity score adjustment was used to balance treatment groups. Results: A total of 7,316 propensity score-matched treatment-naïve patients and 3,524 propensity score-matched treatment-experienced patients were included. Within treatment-naïve patients, those receiving tenofovir showed significantly lower hazards of developing the composite outcome (HR, 0.79; p < 0.0001), hepatocellular carcinoma (HR, 0.86; p = 0.027), mortality (HR, 0.75; p < 0.0001), and liver transplantation (HR, 0.70; p = 0.0189) than those receiving entecavir. As for treatment-experienced patients, tenofovir was associated with a significantly lower risk of the composite outcome (HR, 0.82; p = 0.0033) and hepatocellular carcinoma (HR, 0.60; p < 0.0001), but it did not show a significantly different risk of all-cause mortality (HR, 0.93; p = 0.3374) or liver transplantation (HR, 1.17; p = 0.5112) compared to entecavir. Conclusion: Tenofovir presented a significantly lower incidence of cirrhosis-related complications than entecavir in patients with hepatitis B virus-related cirrhosis. However, no statistically significant difference in death and liver transplantation was seen in treatment-experienced patients.
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Affiliation(s)
- Yu-Han Huang
- Department of Pharmacy, Pingtung Veterans General Hospital, Pingtung, Taiwan
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chuan-Wei Shen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei, Taiwan
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Rinaldi L, Giorgione C, Mormone A, Esposito F, Rinaldi M, Berretta M, Marfella R, Romano C. Non-Invasive Measurement of Hepatic Fibrosis by Transient Elastography: A Narrative Review. Viruses 2023; 15:1730. [PMID: 37632072 PMCID: PMC10459581 DOI: 10.3390/v15081730] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Transient elastography by FibroScan® (Echosens, Paris, France) is a non-invasive method that can provide a reliable measurement of liver fibrosis through the evaluation of liver stiffness. Despite its limitations and risks, liver biopsy has thus far been the only procedure able to provide data to quantify fibrosis. Scientific evidence and clinical practice have made it possible to use FibroScan® in the diagnostic work-up of several liver diseases to monitor patients' long-term treatment response and for complication prevention. For these reasons, this procedure is widely used in clinical practice and is still being investigated for further applications. The aim of this narrative review is to provide a comprehensive overview of the main applications of transient elastography in the current clinical practice.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Chiara Giorgione
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Andrea Mormone
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Francesca Esposito
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Michele Rinaldi
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, “Federico II” University of Naples, 80131 Naples, Italy;
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Ciro Romano
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
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Cho H, Lee YB, Ha Y, Chon YE, Kim MN, Lee JH, Park H, Rim KS, Hwang SG. Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study. BMC Gastroenterol 2023; 23:210. [PMID: 37322445 DOI: 10.1186/s12876-023-02846-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 06/06/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND/AIMS Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.
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Affiliation(s)
- Heejin Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
| | - Yeonjung Ha
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Joo Ho Lee
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Hana Park
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
- Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyu Sung Rim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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Xing Y, Zhong W, Peng D, Han Z, Zeng H, Wang Y, Feng L, Huang J, Xu L, Chen M, Zhou D, Jiang K, Deng X, Zhou H, Tong G. Chinese herbal formula ruangan granule enhances the efficacy of entecavir to reverse advanced liver fibrosis/early cirrhosis in patients with chronic HBV infection: A multicenter, randomized clinical trial. Pharmacol Res 2023; 190:106737. [PMID: 36940891 DOI: 10.1016/j.phrs.2023.106737] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023]
Abstract
BACKGROUND Nucleotide analogs treatment can reverse liver fibrosis in chronic hepatitis B (CHB). However, it has limited effect on fibrosis resolution in patients with CHB, particularly in preventing progression to hepatocellular carcinoma (HCC). Ruangan granule (RG), a Chinese herbal formula, has proven to produce a therapeutic effect against liver fibrosis in animal experiment. Thus, we aimed to evaluate the effect of our Chinese herbal formula (RG) combined with entecavir (ETV) to reverse advanced liver fibrosis/early cirrhosis from CHB. METHODS A total of 240 CHB patients with histologically confirmed advanced liver fibrosis/early cirrhosis from 12 centers were randomly and blindly allocated to consume either ETV (0.5 mg/day) plus RG (2 times/day) or control (ETV) for 48 weeks (wk) treatment. Changes in histopathology, serology and imageology were observed. Liver fibrosis reversion, defined as a reduction in the Knodell HAI score by ≥ 2 points and Ishak score by ≥ 1 grade, was assessed. RESULTS The rate of fibrosis regression and inflammation remission after 48 wk of treatment in histopathology was significantly higher in the ETV + RG group (38.73% vs. 23.94%, P = 0.031). The ultrasonic semiquantitative scores decreased by ≥ 2 points and were 41 (28.87%) and 15 (21.13%) in the ETV+RG and ETV groups, respectively (P = 0.026). The ETV+RG group had a significantly lower Fibrosis-4 score (FIB-4) index (P = 0.028). There was a significant difference between the ETV+RG and ETV groups in the liver function normalization rate (P < 0.01). Moreover, ETV plus RG combination treatment further reduced the risk of HCC in median 55-month follow-up (P < 0.01). CONCLUSIONS This study illustrates that the Chinese herbal formula RG with ETV can improve advanced liver fibrosis/early cirrhosis regression in patients with CHB, further reducing the risk of HCC.
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Affiliation(s)
- Yufeng Xing
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China
| | - Weichao Zhong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China
| | - Deti Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China
| | - Zhiyi Han
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China
| | - Hua Zeng
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Yanqing Wang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China
| | - Lian Feng
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Jinzhen Huang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Linyi Xu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Mingtai Chen
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Daqiao Zhou
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China
| | - Kaiping Jiang
- Department of Hepatology, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong Province, China
| | - Xin Deng
- The First Department of Hepatology, The Third People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Hua Zhou
- Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, Guangdong Province, China.
| | - Guangdong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, China.
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10
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Zhao ZM, Zhu CW, Huang JQ, Li XD, Zhang YX, Liang J, Zhang W, Zhang Y, Jiang XG, Zong YL, Zhang KJ, Sun KW, Zhang B, Lv YH, Xing HC, Xie Q, Liu P, Liu CH. Efficacy and safety of Fuzheng Huayu tablet on persistent advanced liver fibrosis following 2 years entecavir treatment: A single arm clinical objective performance criteria trial. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115599. [PMID: 35932973 DOI: 10.1016/j.jep.2022.115599] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/22/2022] [Accepted: 07/30/2022] [Indexed: 05/25/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Antiviral therapy can alleviate liver fibrosis in chronic hepatitis B, but it has a limited effect on advanced liver fibrosis/cirrhosis. Traditional Chinese medicine (TCM), particularly FuZheng HuaYu (FZHY) tablet, appears to have an antifibrotic effect, but its improving resolution of hepatitis b virus (HBV) -associated advanced fibrosis and experienced anti-viral treatment has not been investigated. AIM OF THE STUDY To observe the safety and efficacy of adjunctive FZHY on the HBV-associated cirrhosis patients who received 2 years of entecavir but still with advanced fibrosis. METHODS An open-label, multicentre, single arm trial. 251 patients were included and treated with TCM consisted of FZHY tablets 1.6 g and granules, three times a day in addition to entecavir 0.5 mg daily for an additional 48 weeks. Primary outcome was regression of fibrosis (the proportion of patients with a 1-point decrease in the Ishak liver fibrosis score from baseline to week 48). RESULTS Fibrosis regression occurred in 94 of 184 patients with paired liver biopsy (51.09%, 95% CI: 43.9～58.0). In 132 compensated cirrhosis patients (Ishak score ≥5), 56.06% (74/132, 95% CI: 47.5～64.2) showed fibrosis regression and reached the goal of 54% (15% more than entecavir mono-therapy). 10 patients occurred adverse reaction, most of them were mild, and all recovered or achieved remission. CONCLUSIONS The combination therapy of FZHY, TCM granules and ETV could regress the liver fibrosis in the patients with HBV cirrhosis, who experienced 2 years of ETV treatment, and it is safe and well tolerated.
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Affiliation(s)
- Zhi-Min Zhao
- Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chuan-Wu Zhu
- Department of Hepatology, The Fifth People's Hospital of Suzhou, Suzhou, 215000, China
| | - Jia-Quan Huang
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiao-Dong Li
- Institute of Liver Diseases, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
| | - Yu-Xi Zhang
- Department of Infectious Diseases, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750021, China
| | - Jian Liang
- Department of Infectious Diseases, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, 530011, China
| | - Wei Zhang
- Institute of Liver Diseases, Shijiazhuang Fifth Hospital, Shijiazhuang, 050021, China
| | - Yong Zhang
- Department of Hepatology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Xian-Gao Jiang
- Department of Infectious Diseases, Wenzhou Central Hospital, Wenzhou, 325000, China
| | - Ya-Li Zong
- Department of Integrated Traditional and Western Medicine, The Ninth Hospital of Nanchang, Nanchang, 330029, China
| | - Ke-Jun Zhang
- Department of Gastroenterology, Jingmen No.1 People's Hospital, Jingmen, 2305654, China
| | - Ke-Wei Sun
- Department of Liver Diseases, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China
| | - Biao Zhang
- Department of Infectious Diseases, Huai'an No. 4 People's Hospital, Huaian, 223002, China
| | - Yun-Hai Lv
- Department of Hepatology, The Fifth People's Hospital of Anyang, Anyang, 455000, China
| | - Hui-Chun Xing
- Center of Hepatology, Beijing Ditan Hospital Capital Medical University, Beijing, 100015, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ping Liu
- Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Cheng-Hai Liu
- Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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11
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Lazar A, Sporea I, Popa A, Lupusoru R, Gherhardt D, Mare R, Apostu A, Hnatiuc M, Șirli R. Dynamic Changes in Liver Stiffness in Patients with Chronic Hepatitis B Undergoing Antiviral Therapy. Diagnostics (Basel) 2022; 12:2646. [PMID: 36359490 PMCID: PMC9689248 DOI: 10.3390/diagnostics12112646] [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: 09/11/2022] [Revised: 10/28/2022] [Accepted: 10/30/2022] [Indexed: 11/16/2022] Open
Abstract
This is a retrospective single-center study that included 87 subjects. All subjects had chronic hepatitis B or HBV cirrhosis and underwent nucleos(t)ide analogs (NUC) treatment for more than one year. The study aimed to evaluate the dynamic changes in liver stiffness (LS) measured by transient elastography (TE) during a median interval of 64 months. Patients were assessed prior to starting therapy and followed up annually. Liver stiffness measurements (LSM) were performed annually, and ten valid LSMs were obtained in each session. Reliable LSMs were defined as the median value of 10 measurements with Interquartile range/median (IQR/M) ≤ 30%. A significant decrease in liver stiffness values (p < 0.001) was observed during follow-up. In patients with liver cirrhosis, the LSMs decreased significantly after only one year, 24.6 ± 4.3 kPa vs. 13.5 ± 4.2 kPa (p = 0.007), whereas the decrease in non-cirrhotic patients was not significant, 7.31 ± 3.62 vs. 6.80 ± 2.41 (p = 0.27). Liver stiffness decrease was more significant in patients with initially higher transaminases. Undetectable viral load was achieved in 73.5% of patients in year one, 82.7% in year two, and 90.8% in year three of treatment. In conclusion, our study reveals a decrease in liver stiffness by TE in patients with chronic hepatitis B when undergoing anti-HBV therapy in the first two years. It can be used as a method for follow-up in patients undergoing NUC therapy.
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Affiliation(s)
- Alin Lazar
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Ioan Sporea
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Alexandru Popa
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Raluca Lupusoru
- Center for Modeling Biological Systems and Data Analysis, Department of Functional Sciences, Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Diana Gherhardt
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Ruxandra Mare
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Alexandru Apostu
- Department of Cardiology, Division of Internal Outpatient Medicine, Prevention and Cardiovascular Recovery, Advanced Research Center of the Institute for Cardiovascular Diseases, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Madalina Hnatiuc
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Roxana Șirli
- Division of Gastroenterology and Hepatology, Center for Advanced Research in Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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12
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Martin P, Nguyen MH, Dieterich DT, Lau DTY, Janssen HLA, Peters MG, Jacobson IM. Treatment Algorithm for Managing Chronic Hepatitis B Virus Infection in the United States: 2021 Update. Clin Gastroenterol Hepatol 2022; 20:1766-1775. [PMID: 34329775 DOI: 10.1016/j.cgh.2021.07.036] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease. METHODS In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in how the natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management. RESULTS This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed. CONCLUSIONS Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described.
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Affiliation(s)
- Paul Martin
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
| | - Mindie H Nguyen
- Department of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California
| | | | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Division of Gastroenterology, NYU Langone Health, New York, New York
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13
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Rong G, Chen Y, Yu Z, Li Q, Bi J, Tan L, Xiang D, Shang Q, Lei C, Chen L, Hu X, Wang J, Liu H, Lu W, Chen Y, Dong Z, Bai W, Yoshida EM, Mendez-Sanchez N, Hu KQ, Qi X, Yang Y. Synergistic Effect of Biejia-Ruangan on Fibrosis Regression in Patients With Chronic Hepatitis B Treated With Entecavir: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. J Infect Dis 2022; 225:1091-1099. [PMID: 32437567 PMCID: PMC8921993 DOI: 10.1093/infdis/jiaa266] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 05/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Long-term nucleos(t)ide analogue (NA) treatment can reverse liver fibrosis in chronic hepatitis B (CHB), but its effect on fibrosis regression remains limited. Biejia-Ruangan (BR) has been approved in China as an antifibrotic traditional Chinese medicine drug in patients with chronic liver diseases. A multicenter randomized controlled trial aims to evaluate the effect of BR on fibrosis regression in CHB patients treated with NAs. METHODS CHB patients with histologically confirmed advanced fibrosis or cirrhosis were randomly assigned to receive entecavir (ETV) (0.5 mg per day) plus BR (2 g 3 times a day) or placebo for 72 weeks. Liver fibrosis regression was defined as a reduction of ≥ 1 point by the Ishak fibrosis stage (IFS). RESULTS Overall, 500 patients were enrolled in each group as the intention-to-treat population. The rate of fibrosis regression after 72 weeks of treatment was significantly higher in the ETV + BR group (40% vs 31.8%; P = .0069). Among 388 patients with cirrhosis (ie, IFS ≥ 5) at baseline, the rate of cirrhosis reversal (ie, IFS ≤ 4) was significantly higher in the ETV + BR group (41.5% vs 30.7%; P = .0103). CONCLUSIONS Addition of BR to the current standard treatment with NAs in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression. CLINICAL TRIALS REGISTRATION NCT01965418.
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Affiliation(s)
- Guanghua Rong
- Department of Liver Diseases & the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Yongping Chen
- Department of Infectious and Liver Diseases, Liver Research Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zujiang Yu
- Department of Infectious Disease, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Qin Li
- Fuzhou Infectious Diseases Hospital, Fuzhou, Fujian Province, China
| | - Jingfeng Bi
- Department of Clinical and Translational Medicine, Fifth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Lin Tan
- Liver Disease Department, Fuyang Second People’s Hospital, Fuyang, Anhui Province, China
| | - Dedong Xiang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qinghua Shang
- Therapeutic Center for Liver Disease, 88th Hospital of People’s Liberation Army, Taian, Shandong Province, China
| | - Chunliang Lei
- Guangzhou Eighth People’s Hospital, Guangzhou, Guangdong Province, China
| | - Liang Chen
- Department of Hepatic Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Xiaoyu Hu
- National Integrative Medicine Clinical Base for Infectious Diseases and Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Jing Wang
- Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
| | - Huabao Liu
- Traditional Chinese Medicine Hospital of Chongqing, Chongqing, China
| | - Wei Lu
- Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Yan Chen
- Department of Liver Diseases & the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Zheng Dong
- Department of Liver Diseases & the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Wenlin Bai
- Department of Liver Diseases & the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Eric M Yoshida
- Division of Gastroenterology, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Nahum Mendez-Sanchez
- Liver Research Unit Medica Sur Clinic and Foundation, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Ke-Qin Hu
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Irvine, Orange, California, USA
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, Liaoning Province, China
| | - Yongping Yang
- Department of Liver Diseases & the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital, Beijing, China
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14
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Chon YE, Kim SU, Seo YS, Lee HW, Lee HA, Kim MN, Roh YH, Park JY, Kim DY, Ahn SH, Tak WY, Park SY, Kim BK. Long-term effects of entecavir and tenofovir treatment on the fibrotic burden in patients with chronic hepatitis B. J Gastroenterol Hepatol 2022; 37:200-207. [PMID: 34478195 DOI: 10.1111/jgh.15678] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Antiviral therapy (AVT) induces fibrosis regression in patients with chronic hepatitis B. We investigated long-term effects of entecavir (ETV) versus tenofovir (TDF) on fibrotic burden. METHODS Treatment-naïve chronic hepatitis B patients who had begun ETV or TDF were recruited from four tertiary hospitals. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were used to determine fibrotic burden. RESULTS In the entire population (n = 3277), although patients treated with ETV had higher baseline APRI (1.71 vs 1.07, P < 0.001) and FIB-4 (3.60 vs 2.80, P < 0.001) than those treated with TDF, significant fibrosis regression was identified during 6 years of AVT in both ETV (APRI, mean 1.71 → 0.48, P < 0.001; FIB-4, mean 3.60 → 2.21, P < 0.001) and TDF groups (APRI, mean 1.07 → 0.43, P < 0.001; FIB-4, mean 2.80 → 2.19, P < 0.001). In patients without cirrhosis (n = 2366), baseline APRI was significantly higher in ETV group than in TDF group (1.72 vs 0.97, P < 0.001); however, they became similar after 6 months. Similarly, baseline FIB-4 was significantly higher in ETV group than in TDF group (3.25 vs 2.35, P < 0.001), but became similar from 4 to 6 years. In patients with cirrhosis (n = 911), baseline APRI (1.70 vs 1.34, P < 0.001) and FIB-4 (4.62 vs 3.91, P = 0.005) were higher in ETV group than in TDF, however, both parameters became statistically similar from 6 months to 6 years. CONCLUSION Significant regression of APRI and FIB-4 was observed during long-term ETV and TDF treatment. Despite higher baseline fibrotic burden in ETV group, fibrotic burden between the groups eventually converged through significant fibrosis regression after 1 to 4 years of AVT.
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Affiliation(s)
- Young Eun Chon
- Department of Internal Medicine, Cha Bundang Medical Center, Cha University, Seongnam, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Mi Na Kim
- Department of Internal Medicine, Cha Bundang Medical Center, Cha University, Seongnam, Republic of Korea
| | - Yun Ho Roh
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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15
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Cho HJ, Choi J, Kim B, Ko J, Choi JI, Huh J, Lee JH, Kim JK. Combining hepatic surface nodularity and serum tests better predicts hepatic fibrosis stages in chronic liver disease. ABDOMINAL RADIOLOGY (NEW YORK) 2021; 46:4189-4199. [PMID: 33977353 DOI: 10.1007/s00261-021-03113-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Hepatic surface nodularity quantified on CT images has shown promising results in staging hepatic fibrosis in chronic hepatitis C. The aim of this study was to evaluate hepatic surface nodularity, serum fibrosis indices, and a linear combination of them for staging fibrosis in chronic liver disease, mainly chronic hepatitis B. METHODS We developed a semiautomated software quantifying hepatic surface nodularity on CT images. Hepatic surface nodularity and serum fibrosis indices were assessed in the development group of 125 patients to generate 3 linear models combining hepatic surface nodularity with the aspartate aminotransferase to platelet ratio index, fibrosis-4 index, or platelet count in reference to the METAVIR scoring system. The models were validated in 183 patients. RESULTS Hepatic surface nodularity and serum fibrosis indices all significantly correlated with fibrosis stages. For binary classifications into cirrhosis (F4), advanced fibrosis (≥ F3), and significant fibrosis (≥ F2), hepatic surface nodularity was significantly different across categories. The areas under the curve (AUCs) of the best model were 0.901, 0.872, and 0.794 for cirrhosis, advanced fibrosis, and significant fibrosis, respectively, higher than serum fibrosis indices alone (0.797-0.802, 0.799-0.818, and 0.761-0.773). In the validation group, the same model likewise showed higher AUCs (0.872, 0.831, and 0.850) compared to serum fibrosis indices (0.722-0.776, 0.692-0.768, and 0.695-0.769; p < 0.001 for F4). CONCLUSION Hepatic surface nodularity combined with serum blood test could be a practical method to predict cirrhosis, advanced fibrosis, and significant fibrosis in chronic liver disease patients, providing higher accuracy than using serum fibrosis indices alone.
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16
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Sadeghi A, Amiri R, Akbarpour E, Mirminachi B, Sharifi AH, Merat S. Changes in liver fibrosis in patients with chronic hepatitis C after successful direct-acting antiviral therapy. Int J Clin Pract 2021; 75:e14145. [PMID: 33709413 DOI: 10.1111/ijcp.14145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/09/2021] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION AND OBJECTIVES After successful treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs), the stage of liver fibrosis decreases over time. Here, we aimed to assess the changes in the liver fibrosis stage using transient elastography (TE) after successful DAA therapy in HCV-infected cirrhotic patients who were referred to Shariati hospital from 2016 to 2017. MATERIAL AND METHODS In this observational cohort, all HCV-infected cirrhotic patients who were treated with a combination of sofosbuvir/daclatasvir, had sustained virologic response (SVR), and had undergone pre- and post-treatment TE, were enrolled. The primary outcome was the changes in TE parameters six months after the end of treatment compared with baseline. RESULTS A total of 442 eligible subjects received DAA therapy. Overall, the SVR rate was 96.6%. Of these, 149 patients had completed the protocol and were enrolled. The mean age of patients was 56.1 ± 10.3 years and the predominant sex was male (77.9%). The median (Q1 -Q3 ) liver stiffness (LS) value at baseline was 26.3 kPa (18.1-38 kPa), which significantly decreased to 20.9 kPa (12-29.7 kPa) [z = -8.45, P-value < .001]. Also, the liver steatosis of patients with baseline CAP ≥ 220 dB/m had a significant response to treatment [z = -2.3, P-value = .023]. Based on multivariate analysis, a higher baseline liver fibrosis stage was the only determinant of LS values improvement in our study. CONCLUSION Successful HCV eradication in patients with liver fibrosis results in significant improvement in LS, even in cirrhotic patients.
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Affiliation(s)
- Anahita Sadeghi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roya Amiri
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Akbarpour
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Mirminachi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir-Houshang Sharifi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahin Merat
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Drew J, Machesky LM. The liver metastatic niche: modelling the extracellular matrix in metastasis. Dis Model Mech 2021; 14:dmm048801. [PMID: 33973625 PMCID: PMC8077555 DOI: 10.1242/dmm.048801] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Dissemination of malignant cells from primary tumours to metastatic sites is a key step in cancer progression. Disseminated tumour cells preferentially settle in specific target organs, and the success of such metastases depends on dynamic interactions between cancer cells and the microenvironments they encounter at secondary sites. Two emerging concepts concerning the biology of metastasis are that organ-specific microenvironments influence the fate of disseminated cancer cells, and that cancer cell-extracellular matrix interactions have important roles at all stages of the metastatic cascade. The extracellular matrix is the complex and dynamic non-cellular component of tissues that provides a physical scaffold and conveys essential adhesive and paracrine signals for a tissue's function. Here, we focus on how extracellular matrix dynamics contribute to liver metastases - a common and deadly event. We discuss how matrix components of the healthy and premetastatic liver support early seeding of disseminated cancer cells, and how the matrix derived from both cancer and liver contributes to the changes in niche composition as metastasis progresses. We also highlight the technical developments that are providing new insights into the stochastic, dynamic and multifaceted roles of the liver extracellular matrix in permitting and sustaining metastasis. An understanding of the contribution of the extracellular matrix to different stages of metastasis may well pave the way to targeted and effective therapies against metastatic disease.
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Affiliation(s)
- James Drew
- CRUK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Laura M. Machesky
- CRUK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
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18
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Abayli B, Abaylı C, Gencdal G. Histopathological evaluation of long-term tenofovir disoproxil fumarate treatment in patients with hepatitis be antigen-negative chronic hepatitis B. World J Gastrointest Pharmacol Ther 2021; 12:32-39. [PMID: 33815864 PMCID: PMC8008959 DOI: 10.4292/wjgpt.v12.i2.32] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/10/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus is a universal health problem. There are approximately 250 million people living with hepatitis B worldwide, and approximately 600000 of these people die every year due to the virus. AIM To compare the pretreatment and post-treatment histopathological results of patients with hepatitis be antigen (HBeAg)-negative chronic hepatitis B (CHB) who had been receiving tenofovir disoproxil fumarate (TDF) treatment at our clinic for at least 5 years. METHODS Patients with HBeAg-negative CHB who were being treated with TDF (245 mg/d) were included in the study. Liver biopsies of patients before TDF treatment and liver biopsies after 5 years of TDF treatment were retrospectively compared. RESULTS A total of 50 HBeAg-negative CHB patients were included in the study (mean age: 47.9 ± 10.4 years, men: 27.54%). Histological improvement was observed in 78% (39) of the patients after 5 years of treatment. After the 5 years of treatment, the mean Ishak score of the patients was 1.3 ± 1.3, and the mean histologic activity index score was 4.1 ± 2.8. A 1.53 point reduction in Ishak fibrosis score was detected after long-term TDF treatment. CONCLUSION Liver biopsies after 5 years of TDF treatment revealed a significant histological response and a regression of the necroinflammatory score compared to pretreatment liver biopsies. To better understand the effects of antiviral treatments on the improvement of liver histology, long-term studies involving larger numbers of patients are needed.
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Affiliation(s)
| | | | - Genco Gencdal
- Department of Gastroenterology, Hepatology and Liver Transplantation, Koc University, School of Medicine, İstanbul 34300, Turkey
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19
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Synthesis of sorafenib analogues incorporating a 1,2,3-triazole ring and cytotoxicity towards hepatocellular carcinoma cell lines. Bioorg Chem 2021; 112:104831. [PMID: 33831675 DOI: 10.1016/j.bioorg.2021.104831] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 02/28/2021] [Accepted: 03/12/2021] [Indexed: 01/07/2023]
Abstract
A series of 1,2,3-triazole-containing Sorafenib analogues, in which the aryl urea moiety of Sorafenib (1) was replaced with a 1,2,3-triazole ring linking a substituted phenoxy fragment, were prepared successfully via Huisgen 1,3-dipolar cycloaddition and nucleophilic aromatic substitution. The studies of cytotoxicity towards human hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh7, indicated that p-tert-butylphenoxy analogue 2m showed significant inhibitory activity against Huh7 with IC50 = 5.67 ± 0.57 µM. More importantly, 2m showed low cytotoxicity against human embryonal lung fibroblast cell line, MRC-5, with IC50 > 100 µM, suggesting its highly selective cytotoxic activity (SI > 17.6) towards Huh7 which is much superior to that of Sorafenib (SI = 6.73). The molecular docking studies revealed that the analogue 2m bound B-RAF near the binding position of Sorafenib, while it interacted VEGFR2 efficiently at the same binding position of Sorafenib. However, 2m exhibited moderate inhibitory activity toward B-RAF, implying that its anti-Huh7 effect might not strictly relate to inhibition of B-RAF. Wound healing and BrdU cell proliferation assays confirmed anti-cell migration and anti-cell proliferative activities towards Huh7. With its inhibitory efficiency and high safety profile, 2m has been identified as a promising candidate for the treatment of HCC.
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20
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Wu X, Zhou J, Sun Y, Ding H, Chen G, Xie W, Piao H, Xu X, Jiang W, Ma H, Ma A, Chen Y, Xu M, Cheng J, Xu Y, Meng T, Wang B, Chen S, Shi Y, Kong Y, Ou X, You H, Jia J. Prediction of liver-related events in patients with compensated HBV-induced cirrhosis receiving antiviral therapy. Hepatol Int 2021; 15:82-92. [PMID: 33460002 DOI: 10.1007/s12072-020-10114-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/18/2020] [Indexed: 10/22/2022]
Abstract
BACKGROUND AND AIMS Many models have been developed to predict liver-related events (LRE) in chronic hepatitis B, few focused on compensated HBV-induced cirrhosis. We aimed to describe the incidence of LRE and to determine independent risk predictors of LRE in compensated HBV-induced cirrhosis patients receiving antiviral therapy using routinely available parameters. METHODS Prospective cohorts of treatment-naïve adults with compensated HBV-induced cirrhosis were enrolled. Patients were treated with entecavir (ETV) or ETV + thymosin-alpha1 (Thy-α1) or lamivudine (LAM) + adefovir (ADV). Data were collected at baseline and every 6 months. LRE was defined as development of decompensation, HCC or death. RESULTS Totally 937 patients were included, 608 patients treated with ETV, 252 with ETV + Thy-α1, and 77 with LAM + ADV. After a median follow-up of 4.5 years, 88 patients developed LRE including 48 with HCC. The cumulative incidence of LRE at year 1, 3, and 5 was 2.1%, 7.0%, and 12.7%, respectively, and was similar for three treatment groups. All models using variables at month 6 or 12 had better fit than models using baseline values. The best model for prediction of LRE used PLT, GGT, and AFP at month 6 [AUC: 0.762 (0.678-0.814)], for hepatic decompensation-PLT, LSM and GGT at month 12 (AUC: 0.834 (0.675-0.919)), and for HCC-AFP and GGT at month 6 [AUC 0.763 (0.691-0.828)]. All models had negative predictive values of 94.0-98.8%. CONCLUSION Models using on-treatment variables are more accurate than models using baseline variables in predicting LRE in patient with compensated HBV-induced cirrhosis receiving antiviral therapy. ClincialTrials.gov number NCT01943617, NCT01720238, NCT03366571, NCT02849132.
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Affiliation(s)
- Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Jialing Zhou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Guofeng Chen
- Division of Liver Fibrosis, The Fifth Medical Center, General Hospital of the People's Liberation Army, Beijing, China
| | - Wen Xie
- Liver Research Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxin Piao
- Office of Clinical Trials, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Xiaoyuan Xu
- Division of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Wei Jiang
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui Ma
- Liver Research Center, Peking University People's Hospital, Beijing, China
| | - Anlin Ma
- Division of Infectious Diseases, China-Japan Friendship Hospital, Beijing, China
| | - Yongpeng Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mingyi Xu
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jilin Cheng
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Shanghai, China
| | - Youqing Xu
- Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tongtong Meng
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Bingqiong Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Shuyan Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Yiwen Shi
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Yuanyuan Kong
- National Clinical Research Center of Digestive Disease, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.
- National Clinical Research Center of Digestive Disease, Beijing, China.
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.
- National Clinical Research Center of Digestive Disease, Beijing, China.
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China.
- National Clinical Research Center of Digestive Disease, Beijing, China.
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21
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Huang C, Liu L, Wang H, Fang M, Feng H, Li Y, Wang M, Tong L, Xiao X, Wang Z, Xu X, He Y, Gao C. Serum N-glycan fingerprint nomogram predicts liver fibrosis: a multicenter study. Clin Chem Lab Med 2021; 59:1087-1097. [PMID: 33554541 DOI: 10.1515/cclm-2020-1588] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/11/2020] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Liver cirrhosis (LC) is the end-stage of fibrosis in chronic liver diseases, non-invasive early detection of liver fibrosis (LF) is particularly essential for therapeutic decision. Aberrant glycosylation of glycoproteins has been demonstrated to be closely related to liver abnormalities. METHODS This study was designed to enroll a total of 1,565 participants with LC/LF, chronic hepatitis virus (CHB) and healthy controls. Fibrosis was confirmed by liver biopsy. Using capillary electrophoresis N-glycan fingerprint (NGFP) analysis, we developed a nomogram algorithm (FIB-G) to discriminate LC from non-cirrhotic subjects. RESULTS The FIB-G demonstrated good diagnostic performances in identifying LC with the area under the curve (AUC) 0.895 (95%CI: 0.857-0.915). Furthermore, the diagnostic efficiencies of FIB-G were superior to that of log (P2/P8), procollagen III N-terminal (PIIINP), type IV collage (IV-C), laminin (LN), hyaluronic acid (HA), aspartate transaminase to platelets ratio index (APRI), and FIB-4 when detecting significant fibrosis (S0-1 vs. S2-4, AUC: 0.787, 95%CI: 0.701-0.873), severe fibrosis (S0-2 vs. S3-4, AUC: 0.844, 95%CI: 0.763-0.924), and LC (S0-3 vs. S4, AUC: 0.773, 95%CI: 0.667-0.880). Besides, changes of FIB-G were associated well with the regression of fibrosis and liver function Child-Pugh classification. CONCLUSIONS FIB-G is an accurate multivariant N-glycomic algorithm for LC prediction and fibrosis progression/regression monitoring. The high throughput feasible NGFP using only 2 μL of serum could help physicians make the more precise non-invasive staging of LF or cirrhosis and reduce the need for invasive liver biopsy.
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Affiliation(s)
- Chenjun Huang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Lijuan Liu
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Hao Wang
- Department of Laboratory Medicine, Shanghai Changzheng Hospital, Shanghai, P.R. China
| | - Meng Fang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Huijuan Feng
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Ya Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Mengmeng Wang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China.,Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
| | - Lin Tong
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Xiao Xiao
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Ziyi Wang
- Department of Data Analysis, Wonders Information Co. LTD., Shanghai, P.R. China
| | - Xuewen Xu
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Yutong He
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Chunfang Gao
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
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22
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Johnson PJ, Berhane S, Walker AJ, Gordon FH, Ryder SD, McPherson S, Sreedharan A, Ustianowski AA, Agarwal K, Mutimer D, Kumada T, Toyoda H, Irving WL. Impact of direct-acting antiviral agents on liver function in patients with chronic hepatitis C virus infection. J Viral Hepat 2021; 28:168-176. [PMID: 32978982 DOI: 10.1111/jvh.13408] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022]
Abstract
Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3 years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.
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Affiliation(s)
- Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Sarah Berhane
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Alex J Walker
- Centre for Evidence Based Medicine, Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | | | - Steven D Ryder
- Nottingham University Hospitals NHS Trust, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Stuart McPherson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - David Mutimer
- University Hospitals Birmingham NHS Foundation Trust Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, UK
| | - Takeshi Kumada
- Department of Nursing, Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - William L Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
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23
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Wei H, Song B. Elastography for Longitudinal Assessment of Liver Fibrosis after Antiviral Therapy: A Review. J Clin Transl Hepatol 2020; 8:445-453. [PMID: 33447528 PMCID: PMC7782123 DOI: 10.14218/jcth.2020.00033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 07/23/2020] [Accepted: 08/10/2020] [Indexed: 02/05/2023] Open
Abstract
Chronic hepatitis B or C viral infection is a common cause of liver cirrhosis and hepatocellular carcinoma. Fibrosis regression can be achieved after long-term antiviral therapy (AVT). Monitoring of dynamic changes in liver fibrosis after treatment is essential for establishing prognosis and formulation of a follow-up surveillance program. Routine surveillance of fibrosis after AVT by liver biopsy, the gold standard for fibrosis assessment, is hindered by its invasive nature, sampling error and observer variability. Elastography is a noninvasive quantitative alternative that has been widely used and validated for the staging of liver fibrosis prior to treatment. Recently, increasing research interest has been focused on the role of elastography in longitudinal assessment of liver fibrosis after AVT. In this review, the basic principles, acquisition techniques, diagnostic performances, and strengths and limitations of ultrasound elastography and magnetic resonance elastography are presented. Emerging evidence regarding the use of elastography techniques for the monitoring of liver fibrosis after AVT is summarized. Current challenges and future directions are also discussed, designed to optimize the application of these techniques in clinical practice.
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Affiliation(s)
- Hong Wei
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Bin Song
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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24
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Odagiri N, Matsubara T, Sato-Matsubara M, Fujii H, Enomoto M, Kawada N. Anti-fibrotic treatments for chronic liver diseases: The present and the future. Clin Mol Hepatol 2020; 27:413-424. [PMID: 33317250 PMCID: PMC8273638 DOI: 10.3350/cmh.2020.0187] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/07/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis reflects tissue scarring in the liver due to the accumulation of excessive extracellular matrix in response to chronically persistent liver injury. Hepatocyte cell death can trigger capillarization of liver sinusoidal endothelial cells, stimulation of immune cells including macrophages and Kupffer cells, and activation of hepatic stellate cells (HSCs), resulting in progression of liver fibrosis. Liver cirrhosis is the terminal state of liver fibrosis and is associated with severe complications, such as liver failure, portal hypertension, and liver cancer. Nevertheless, effective therapy for cirrhosis has not yet been established, and liver transplantation is the only radical treatment for severe cases. Studies investigating HSC activation and regulation of collagen production in the liver have made breakthroughs in recent decades that have advanced the knowledge regarding liver fibrosis pathophysiology. In this review, we summarize molecular mechanisms of liver fibrosis and discuss the development of novel anti-fibrotic therapies.
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Affiliation(s)
- Naoshi Odagiri
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Misako Sato-Matsubara
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.,Department of Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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25
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Peng D, Xing HY, Li C, Wang XF, Hou M, Li B, Chen JH. The clinical efficacy and adverse effects of Entecavir plus Thymosin alpha-1 combination therapy versus Entecavir Monotherapy in HBV-related cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol 2020; 20:348. [PMID: 33076834 PMCID: PMC7574490 DOI: 10.1186/s12876-020-01477-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023] Open
Abstract
Background Previous studies have demonstrated the benefits of thymosin alpha-1 (Tα1) in anti-virus, immunological enhancement and anti-inflammation. However, it is controversial about the efficacy and safety of entecavir (ETV) plus Tα1 combination therapy versus ETV monotherapy in cirrhotic patients with hepatitis B virus (HBV) infection. Methods The systematic review and meta-analysis of randomized clinical trials (RCTs) were performed to evaluate the efficacy and safety of ETV plus Tα1 combination therapy versus ETV monotherapy in HBV-related patients with cirrhosis. We performed a systematic literature search via PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), and Chinese Biological Medicine database (CBM). Relative risk (RR) and standardized mean difference (SMD) with a fixed- or random- effect model were calculated. Heterogeneity was assessed through a Cochrane Q-test and I2 values. Results Seven RCTs involving 1144 subjects were included in the systematic review and meta-analysis. Compared with ETV monotherapy, ETV plus Tα1 combination therapy led to a higher complete response (RR = 1.18; 95% CI, 1.07–1.30). In post treatment for 24 weeks, the HBV DNA undetectable rate and HBeAg loss rate were higher in ETV plus Tα1 group than in ETV alone group (RR = 1.91; 95% CI, 1.56–2.35; RR = 2.05; 95% CI, 1.62–2.60). However, after 48 and 52 weeks of treatment, there was no significant difference between the combination therapy and ETV monotherapy (RR = 1.07; 95% CI, 0.96–1.18; RR = 1.17; 95% CI, 0.89–1.55). At week 52 of treatment, the HBsAg loss rate of ETV plus Tα1 group was no significance with that of ETV alone group (RR = 1.03; 95% CI, 0.15–7.26). In comparison with ETV alone, the some biochemical parameters and liver fibrosis were obviously improved by ETV plus Tα1, and there was significant heterogeneity. In addition, the number of adverse events was significantly reduced by ETV plus Tα1, compared to ETV alone (RR = 0.48; 95% CI, 0.24–0.95). Conclusions ETV plus Tα1 might lead to a higher clinical response and a lower comprehensive adverse reaction rate in HBV-related patients with cirrhosis, compared to ETV alone. However, the whole patients included in this meta-analysis were from Chinese mainland, so that more worldwide RCTs with a larger sample size are needed to verify the current findings.
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Affiliation(s)
- Dan Peng
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Hai-Yan Xing
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Chen Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xian-Feng Wang
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Min Hou
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Bin Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Jian-Hong Chen
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China.
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26
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Recompensation of Decompensated Hepatitis B Cirrhosis: Current Status and Challenges. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9609731. [PMID: 33029534 PMCID: PMC7527887 DOI: 10.1155/2020/9609731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/07/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023]
Abstract
Liver-function decompensation or hepatocellular carcinoma (HCC) gradually appears after chronic hepatitis B progresses to cirrhosis. Effective antiviral treatment can significantly improve the long-term prognosis of decompensated patients, and some patients present recompensation of decompensated hepatitis B cirrhosis. At present, there are limited research data on the recompensation of decompensated hepatitis B cirrhosis. There is still controversy regarding the evaluation time, evaluation indicators, influencing factors, and long-term prognosis of recompensation.
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27
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Chen Y, Zhao Z, Fan H, Li Z, He Y, Liu C. Safety and therapeutic effects of anti-fibrotic Traditional Chinese Medicine Fuzheng Huayu on persistent advanced stage fibrosis following 2 years entecavir treatment: Study protocol for a single arm clinical objective performance criteria trial. Contemp Clin Trials Commun 2020; 19:100601. [PMID: 32642592 PMCID: PMC7334581 DOI: 10.1016/j.conctc.2020.100601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 06/09/2020] [Accepted: 06/21/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is an important etiology for chronic hepatitis globally, and especially so in China. HBV infection can lead to the development of cirrhosis through the pathological process of liver fibrosis. The effective suppression of HBV replication with NAs or interferon-alpha can histologically regress the fibrotic pathological process, but there remain patients who have achieved anti-viral responses and normalization of serum liver tests, but not liver fibrosis regression. This subset of patients typically presents with advanced liver fibrosis at baseline. Therefore, it is reasonable to administer the anti-fibrotic agents, coupled with antivirals for patients with advanced liver fibrosis due to HBV, in order to improve the fibrotic regression of the patients. Fuzheng Huayu (FZHY) tablet is a botanical product with evidence demonstrating its efficacy against mild to moderate liver fibrosis. The current clinical trial evaluates the efficacy and safety of the combination therapy of traditional Chinese medicine (TCM) (FZHY and herbal granule) and entecavir for HBV compensated cirrhosis. We will enroll HBV patients who presented with a good viral response after 2 years of entecavir treatment but had advanced liver fibrosis (≥Ishak F5). METHODS This is a single-arm clinical trial, conducted in 20 centers in mainland China over a period of 60 weeks, including 48 weeks of treatment observation and 12 weeks of follow-up. The main inclusion criteria include HBsAg positive more than 6 months, 2 years administration of entecavir, HBV DNA less than 20 IU/ml, liver fibrotic stage ≥ F5, and Child-Pugh scoring <7 (Stage A). The sample size is estimated to be about 190, considering a 20% drop-out and 60% of patient's compliance for the second liver biopsy so a total of 350 participants will be enrolled. All eligible participants are divided into 3 subgroups according to the TCM clinic pattern. And all patients will take 1 Entecavir tablet (0.5 mg) per day, 4 FZHY tablets (1.6 g) three times a day, and specific TCM granule three times a day, which is decided by TCM clinical patterns (CPs) differentiation. The patients were treated for 48 weeks, and follow-up visits at 12, 24, 36, 48 weeks and 60 weeks. The patients will receive the second liver biopsy at the end of 48 weeks, with a 12 weeks follow-up after that.The primary endpoint is the proportion of subjects with a 1-point improvement of liver fibrosis stage using the Ishak score from baseline to week 48 in the study, according to consensus readings evaluated by a panel of hepato-pathologists. The secondary endpoints are the brightness-mode ultrasonic, fibrotic biomarkers. The adverse events (AEs) will be recorded for 60 weeks, and the safety of the combination therapy will be evaluated. Meanwhile, the efficacy in the 3 sub-groups will be stratified and analyzed. DISCUSSION The study has been designed to test the therapeutic effects and safety of the combination therapy of FZHY and herbal granule with entecavir on persistent advanced stage fibrosis/cirrhosis following 2 years entecavir treatment, and to explore an effective integrative therapy on HBV cirrhosis. TRIAL REGISTRATION ClinicalTrials.gov. NCT02241616. Registered on September 16, 2014.
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Key Words
- AEs, adverse events
- CPs, Clinical Patterns
- CRC, Clinical Research Coodinator
- CRO, Central Clinical Research Organization
- Cirrhosis
- EDC, Electronic Data Collection
- Entecavir
- FZHY, FuZheng HuaYu
- Fuzheng huayu tablet
- GMP, Good Manufacturing Practice
- HBV, Hepatitis B virus
- HSCs, Hepatic Stellate Cells
- Hepatitis B virus
- Liver fibrosis
- NAs, Nucleos(t)ide analogues
- NMPA, National Medical Products Administration
- OPC, objective performance criteria
- PDGF-BB, Platelet Derived Growth Factor-BB
- PHBC-PRO, patient reported outcomes of post-hepatitic B cirrhosis
- PI, principal investigator
- Regression
- TCM, Traditional Chinese medicine
- TGF-β1, Transforming Growth Factor-beta 1
- US FDA, United States Food and Drug Administration
- WHO, World Health Organization
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Affiliation(s)
- Yangyi Chen
- ZhangHeng Rd, NO.528, PuDong New Area, Shanghai, 201203, China
| | - Zhimin Zhao
- ZhangHeng Rd, NO.528, PuDong New Area, Shanghai, 201203, China
| | - Haina Fan
- ZhangHeng Rd, NO.528, PuDong New Area, Shanghai, 201203, China
| | - Zhengxin Li
- ZhangHeng Rd, NO.528, PuDong New Area, Shanghai, 201203, China
| | - Yingchun He
- ZhangHeng Rd, NO.528, PuDong New Area, Shanghai, 201203, China
| | - Chenghai Liu
- ZhangHeng Rd, NO.528, PuDong New Area, Shanghai, 201203, China
- Cailun Rd, No. 1200, Pudong New Area, Shanghai, 201203, China
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Arteel GE, Naba A. The liver matrisome - looking beyond collagens. JHEP Rep 2020; 2:100115. [PMID: 32637906 PMCID: PMC7330160 DOI: 10.1016/j.jhepr.2020.100115] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/17/2020] [Accepted: 03/22/2020] [Indexed: 02/07/2023] Open
Abstract
The extracellular matrix (ECM) is a diverse microenvironment that maintains bidirectional communication with surrounding cells to regulate cell and tissue homeostasis. The classical definition of the ECM has more recently been extended to include non-fibrillar proteins that either interact or are structurally affiliated with the ECM, termed the 'matrisome.' In addition to providing the structure and architectural support for cells and tissue, the matrisome serves as a reservoir for growth factors and cytokines, as well as a signaling hub via which cells can communicate with their environment and vice-versa. The matrisome is a master regulator of tissue homeostasis and organ function, which can dynamically and appropriately respond to any stress or injury. Failure to properly regulate these responses can lead to changes in the matrisome that are maladaptive. Hepatic fibrosis is a canonical example of ECM dyshomeostasis, leading to accumulation of predominantly collagenous ECM; indeed, hepatic fibrosis is considered almost synonymous with collagen accumulation. However, the qualitative and quantitative alterations of the hepatic matrisome during fibrosis are much more diverse than simple accumulation of collagens and occur long before fibrosis is histologically detected. A deeper understanding of the hepatic matrisome and its response to injury could yield new mechanistic insights into disease progression and regression, as well as potentially identify new biomarkers for both. In this review, we discuss the role of the ECM in liver diseases and look at new "omic" approaches to study this compartment.
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Key Words
- AUROC, area under the receiver operating characteristic curve
- CCl4, carbon tetrachloride
- ECM
- ECM, extracellular matrix
- Extracellular matrix
- Fibrosis
- HCC, hepatocellular carcinoma
- Liver disease
- MMP, matrix metalloproteinase
- NAFLD, non-alcoholic fatty liver disease
- NPV, negative predictive value
- POSTN, periostin
- PPV, positive predictive values
- Proteomics
- Regeneration
- TGFβ, transforming growth factor beta
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Affiliation(s)
- Gavin E. Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, Pittsburgh, PA, USA
| | - Alexandra Naba
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
- University of Illinois Cancer Center, Chicago, IL, USA
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Comparative Study of PLGA in-situ Implant and Nanoparticle Formulations of Entecavir; in-vitro and in-vivo evaluation. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101585] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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30
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Lin N, Yao Z, Xu L, Xu M, Yuan L, Zhuang H, Lin Y, Xu R. Bone marrow-derived mesenchymal stem cells utilize the notch signaling pathway to induce apoptosis of hepatic stellate cells via NF-κB sensor. Biol Chem 2020; 401:505-515. [PMID: 31527287 DOI: 10.1515/hsz-2019-0248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 08/13/2019] [Indexed: 01/26/2023]
Abstract
The present study aimed at evaluating the mechanism by which functionality of hepatic stellate cells (HSCs) is modulated by bone marrow stromal cells (BMSCs). Induction of apoptosis in HSCs was found to be caused by directly co-culturing HSCs with BMSCs, where the expression of α-smooth muscle actin (α-SMA) increased significantly in HSCs, along with an increase in their proliferation rate. Additionally, expression of Hes1 and Notch1 in HSCs co-cultured with BMSCs increased significantly at both protein and mRNA levels. Blocking of the notch signaling pathway (NSP) either by Notch1 siRNA or by DAPT treatment increased the proliferation rate while decreasing apoptosis and led to activation of the NF-κB signaling pathway in HSCs co-cultured with BMSCs. These effects were found to be reversed in HSCs overexpressing IκB S32/S36 mutants. The Notch signaling-mediated cell-cell contact was partially involved in the significant inhibition of proliferation of HSCs by BMSCs. Additionally, the NF-κB pathway was found to be responsible for NSP-mediated inhibition of growth of HSCs in the co-culture system. Thus, BMSCs might have a potential therapeutic significance in treating hepatic fibrosis.
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Affiliation(s)
- Nan Lin
- Department of Hepatobilliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong, China
| | - Zhicheng Yao
- Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Linan Xu
- Department of Reproductive Medicine Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Mingxin Xu
- Department of Hepatobilliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong, China
| | - Lin Yuan
- Department of Hepatobilliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong, China
| | - Haiyun Zhuang
- Department of Hepatobilliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong, China
| | - Yang Lin
- Department of Hepatobilliary Surgery, The Kashi Affiliated Hospital of Sun Yat-sen University, Kashi, Xinjiang, China
| | - Ruiyun Xu
- Department of Hepatobilliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong, China
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31
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Wei H, Jiang HY, Li M, Zhang T, Song B. Two-dimensional shear wave elastography for significant liver fibrosis in patients with chronic hepatitis B: A systematic review and meta-analysis. Eur J Radiol 2020; 124:108839. [PMID: 31981878 DOI: 10.1016/j.ejrad.2020.108839] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 02/05/2023]
Abstract
PURPOSE To determine the diagnostic performance and cutoff value of two-dimensional shear wave elastography (2D SWE) for detecting significant liver fibrosis in patients with chronic hepatitis B (CHB). METHODS A systematic literature search of the PubMed, EMBASE, Cochrane Library databases and Web of Science was conducted. Bivariate modelling and summary receiver-operating-characteristic (ROC) modelling were constructed to summarize the diagnostic performance of 2D SWE. Meta-regression analyses were performed to explore the source of heterogeneity. RESULTS Eleven eligible studies with 2623 patients were included. 2D SWE showed a summary sensitivity of 88 % (95 % CI: 83-91), specificity of 83 % (95 % CI: 78-88) and area under the ROC curve of 0.92 (95 % CI: 0.89-0.94) for detecting significant fibrosis in CHB patients. The mean threshold of 2D SWE was 7.91 kPa (range: 6.73-10.00 kPa). Notably, the cutoffs of studies excluding patients with history of prior antiviral therapy were generally lower than that of studies without excluding those who had received antiviral treatment, with an average of 7.15 kPa and 8.87 kPa, respectively (p < 0.01). Meta-regression analysis revealed that enrollment of consecutive patients was the only significant factor influencing heterogeneity (p < 0.01). Specifically, studies recruiting consecutive patients with CHB had significantly lower sensitivity than those with absence of consecutive enrolment (0.83 vs 0.92, p < 0.01). CONCLUSIONS 2D SWE is an excellent modality for predicting significant liver fibrosis in CHB populations. Further work is required to establish the cutoffs that account for antiviral treatment as a potential confounding factor.
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Affiliation(s)
- Hong Wei
- Department of Radiology, Sichuan University West China Hospital, Chengdu, Sichuan Province, China
| | - Han-Yu Jiang
- Department of Radiology, Sichuan University West China Hospital, Chengdu, Sichuan Province, China
| | - Mou Li
- Department of Radiology, Sichuan University West China Hospital, Chengdu, Sichuan Province, China
| | - Tong Zhang
- Department of Radiology, Sichuan University West China Hospital, Chengdu, Sichuan Province, China
| | - Bin Song
- Department of Radiology, Sichuan University West China Hospital, Chengdu, Sichuan Province, China.
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Trivella JP, Martin P, Carrion AF. Novel targeted therapies for the management of liver fibrosis. Expert Opin Emerg Drugs 2020; 25:59-70. [PMID: 32098512 DOI: 10.1080/14728214.2020.1735350] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 02/24/2020] [Indexed: 12/11/2022]
Abstract
Introduction: Prolonged liver injury results in tissue damage and replacement by extracellular matrix and fibrosis. Cirrhosis represents a leading cause of mortality worldwide and imposes a major financial burden on health-care systems. Fortunately, fibrogenesis has proven to be reversible if halted early, encouraging the development of novel anti-fibrotic agents that may accelerate histological restoration. Preclinical data have elucidated numerous potential therapeutic targets and many anti-fibrotic agents are currently at various stages of clinical research.Areas covered: The present review summarizes recent clinical data regarding anti-fibrotic drugs including monoclonal antibodies, targeted conjugates, and small molecule agents.Expert opinion: Although undeniable progress has been made in the development of anti-fibrotic agents in recent years, most data currently available are derived from preclinical and early clinical studies. The efficacy and safety of these agents will need to be corroborated by larger clinical trials, some of which are ongoing with results expected in the upcoming years. Combination therapy with agents targeting different pathways of fibrogenesis will also be of great interest for the future and will need to be explored in clinical trials.
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Affiliation(s)
- Juan P Trivella
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Paul Martin
- Division of Gastroenterology and Hepatology, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Andres F Carrion
- Division of Gastroenterology and Hepatology, University of Miami, Miller School of Medicine, Miami, FL, USA
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Alsebaey A, Badr R, Abdelsameea E, Amer MO, Eljaky MA, El-Azab G, Salama M. King’s Fibrosis, Fibrosis Index, GPR, and ALBI Score Are Useful Models for Liver Fibrosis in Chronic Hepatitis B Patients Pre- and Post-Treatment. HEPATITIS MONTHLY 2019; 19. [DOI: 10.5812/hepatmon.96081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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34
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Saab S, Song D, Challita YP, Xiwen Zhou T, Saab EG, Viramontes MR, Choi G, Durazo FA, Han SB, El Kabany MM, Jackson NJ, Busuttil RW. Long-term outcomes with oral therapy in liver transplant recipients with hepatitis B. Clin Transplant 2019; 33:e13740. [PMID: 31651048 DOI: 10.1111/ctr.13740] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 10/14/2019] [Accepted: 10/20/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND The long-term impact of oral hepatitis B antiviral therapy in liver transplant (LT) recipients is currently underexplored. The objective of this study was to evaluate how oral antiviral agents impact long-term renal function in this population. METHODS We studied 79 patients who received a LT for hepatitis B and were placed on all-oral antiviral therapy after withdrawing from hepatitis B immune globulin therapy at the University of California, Los Angeles. Laboratory data were obtained through a retrospective chart review. Univariate analysis and two-sided t tests were performed. RESULTS The mean (±SD [standard deviation]) age at the time of LT was 65.4 (± 8.2) years. The overall mean (±SD) follow-up from LT was 6.5 (±3.3) years. 22.8% (18/79) of recipients on all-oral therapy had worsening of their chronic kidney disease stage, and 17.7% (14/79) had an increase in creatinine of at least 0.3 mg/dL. There were no significant changes in creatinine and GFR in patients while on tenofovir alafenamide. Patient survival was decreased for recipients who developed detectable HBsAg. CONCLUSION Tenofovir alafenamide appears to have less of an impact on renal function in LT recipients than other antiviral agents. HBV recurrence after transplant is associated with decreased patient survival and remains an important issue to address for LT recipients on oral antiviral therapy.
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Affiliation(s)
- Sammy Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, California.,Department of Medicine, University of California at Los Angeles, Los Angeles, California.,Department of Nursing, University of California at Los Angeles, Los Angeles, California
| | - Dana Song
- Department of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Youssef P Challita
- Department of Surgery, University of California at Los Angeles, Los Angeles, California
| | - Tina Xiwen Zhou
- Department of Surgery, University of California at Los Angeles, Los Angeles, California
| | - Elena G Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, California
| | - Matthew R Viramontes
- Department of Surgery, University of California at Los Angeles, Los Angeles, California
| | - Gina Choi
- Department of Surgery, University of California at Los Angeles, Los Angeles, California.,Department of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Francisco A Durazo
- Department of Surgery, University of California at Los Angeles, Los Angeles, California.,Department of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Steven B Han
- Department of Surgery, University of California at Los Angeles, Los Angeles, California.,Department of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Mohammed M El Kabany
- Department of Surgery, University of California at Los Angeles, Los Angeles, California.,Department of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Nicholas J Jackson
- Department of Medicine Statistics Core, University of California at Los Angeles, Los Angeles, California
| | - Ronald W Busuttil
- Department of Surgery, University of California at Los Angeles, Los Angeles, California
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Wu Z, Gong Y, Peng J, Zhang X, Tang L. Correlation Between Serum Entecavir Concentration and Virological Response in Patients with Chronic Type B Hepatitis. Med Sci Monit 2019; 25:6998-7004. [PMID: 31530794 PMCID: PMC6765337 DOI: 10.12659/msm.916553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background This study was conducted to investigate the relationship between trough concentrations of serum entecavir and the virological response of patients with chronic type B hepatitis (CHB). Material/Methods A total of 59 CHB patients who had been receiving antiviral therapy with entecavir for >3 months were included in this study. Serum entecavir concentrations, HBV DNA levels, and other biochemical indicators were determined after drug treatments. Results The serum entecavir concentrations in the good response and poor response groups were 0.58±0.38 and 0.43±0.15 ng/mL, respectively. The antiviral efficacy was 52.38%, 65.63%, and 100% in low, middle, and high entecavir groups, respectively. The baseline HBV DNA level among the patients with poor response was significantly higher than in the group with good response. Among the 14 patients with a high viral load, 5 patients showed a good response and had a higher entecavir concentration than the other 9 patients with poor response. Entecavir in patients with cirrhosis was higher than in those without cirrhosis (0.63±0.45 ng/mL vs. 0.46±0.16 ng/mL), and the virological response rate in patients with cirrhosis was higher than in those without cirrhosis (83.33 vs. 51.43%). Cirrhosis progression was reversed in 3 patients with high serum entecavir concentration. Conclusions Serum entecavir concentrations vary among individuals, and higher serum entecavir concentration is correlated with more efficient viral clearance. Therefore, for patients with poor response, high doses may be beneficial for viral clearance.
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Affiliation(s)
- Zhengjie Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Yiwen Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Jun Peng
- Hangzhou Biozon Medical Institute, Hangzhou, Zhejiang, China (mainland)
| | - Xiao Zhang
- Hangzhou Biozon Medical Institute, Hangzhou, Zhejiang, China (mainland)
| | - Lingling Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland)
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Moscoso CG, Steer CJ. "Let my liver rather heat with wine" - a review of hepatic fibrosis pathophysiology and emerging therapeutics. Hepat Med 2019; 11:109-129. [PMID: 31565001 PMCID: PMC6731525 DOI: 10.2147/hmer.s213397] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/17/2019] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis is characterized by extensive hepatic fibrosis, and it is the 14th leading cause of death worldwide. Numerous contributing conditions have been implicated in its development, including infectious etiologies, medication overdose or adverse effects, ingestible toxins, autoimmunity, hemochromatosis, Wilson’s disease and primary biliary cholangitis to list a few. It is associated with portal hypertension and its stigmata (varices, ascites, hepatic encephalopathy, combined coagulopathy and thrombophilia), and it is a major risk factor for hepatocellular carcinoma. Currently, orthotopic liver transplantation has been the only curative modality to treat cirrhosis, and the scarcity of donors results in many people waiting years for a transplant. Identification of novel targets for pharmacologic therapy through elucidation of key mechanistic components to induce fibrosis reversal is the subject of intense research. Development of robust models of hepatic fibrosis to faithfully characterize the interplay between activated hepatic stellate cells (the principal fibrogenic contributor to fibrosis initiation and perpetuation), hepatocytes and extracellular matrix components has the potential to identify critical components and mechanisms that can be exploited for targeted treatment. In this review, we will highlight key cellular pathways involved in the pathophysiology of fibrosis from extracellular ligands, effectors and receptors, to nuclear receptors, epigenetic mechanisms, energy homeostasis and cytokines. Further, molecular pathways of hepatic stellate cell deactivation are discussed, including apoptosis, senescence and reversal or transdifferentiation to an inactivated state resembling quiescence. Lastly, clinical evidence of fibrosis reversal induced by biologics and small molecules is summarized, current compounds under clinical trials are described and efforts for treatment of hepatic fibrosis with mesenchymal stem cells are highlighted. An enhanced understanding of the rich tapestry of cellular processes identified in the initiation, perpetuation and resolution of hepatic fibrosis, driven principally through phenotypic switching of hepatic stellate cells, should lead to a breakthrough in potential therapeutic modalities.
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Affiliation(s)
- Carlos G Moscoso
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition
| | - Clifford J Steer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition.,Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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Li G, Zhang Q, Yu Y, Qiu C, Zhang H, Zhang M, Song Z, Yang Y, Hong J, Lu J, Li N, Tang Q, Xu L, Wang X, Zhang W, Chen Z. Histological responses of peginterferon alpha add-on therapy in patients with chronic hepatitis B with advanced liver fibrosis after long-term nucleos(t)ide analog treatment. J Viral Hepat 2019; 26 Suppl 1:50-58. [PMID: 31380590 DOI: 10.1111/jvh.13152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 01/05/2023]
Abstract
Although long-term antiviral treatment with nucleos(t)ide analogs (NAs) can lead to histological improvement in patients with chronic hepatitis B (CHB), a substantial proportion of patients still fail to achieve regression of fibrosis. Here, we investigated whether peginterferon alpha (Peg-IFNα） add-on therapy had benefits on fibrosis regression in patients with sustained severe fibrosis even after long-term NA treatment. We conducted a retrospective analysis of data from 50 patients with CHB receiving 48 weeks of Peg-IFNα add-on therapy. All enrolled patients had advanced fibrosis or cirrhosis (S score ≥ 3) at baseline and underwent NA treatment for at least 1 year before Peg-IFNα addition. Paired liver biopsies before and after Peg-IFNα add-on treatment and laboratory tests at baseline, 24 weeks of treatment, 48 weeks of treatment and long-term follow-up were analysed. Of the 50 patients enrolled in this study, 34 patients (68.0%) had significant regression of fibrosis, and 42 (84.0%) showed significant remission of inflammation after Peg-IFNα add-on treatment. Compared with nonresponders, patients with significant histological improvement showed faster hepatitis B surface antigen (HBsAg) decline and tended to have higher cumulative hepatitis B e antigen (HBeAg) and HBsAg loss rates during long-term follow-up. Peg-IFNα add-on therapy led to significant regression of fibrosis and resolution of inflammation in patients with advanced fibrosis after long-term NA treatment.
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Affiliation(s)
- Guojun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Qiran Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiqi Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhangzhang Song
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Yusheng Yang
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Jiemin Hong
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Niuniu Li
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Quanzhen Tang
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Long Xu
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Xuanyi Wang
- Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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Zhang Q, Li G, Yu Y, Qiu C, Zheng J, Zhang H, Zhang M, Song Z, Yang Y, Du X, Hong J, Lu J, Li N, Tang Q, Xu L, Wang X, Huang Y, Zhang J, Chen Z, Zhang W. Histological response to combination therapy with nucleos(t)ide analogs and peginterferon alpha in treatment-naïve chronic hepatitis B patients. J Viral Hepat 2019; 26 Suppl 1:59-68. [PMID: 31380588 DOI: 10.1111/jvh.13153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 12/09/2022]
Abstract
Although nucleos(t)ide analog (NA) monotherapy is effective in hepatitis B virus suppression and fibrosis regression, serological response rates are not satisfactory. Studies assessing the benefits of combination therapy with NAs and peginterferon alpha (PegIFNα) in patients with chronic hepatitis B (CHB) have produced conflicting results and mainly focused on serological outcomes. Histological changes in response to combination therapy have not been evaluated in real-world practice. This study aimed to evaluate the histological changes in response to NA-PegIFNα combination therapy in CHB patients and to comprehensively compare the efficacy of NA-PegIFNα combination therapy and NA monotherapy. We conducted a retrospective analysis of data from 40 CHB patients who underwent either NA-PegIFNα combination therapy or NA monotherapy. Changes in histology at 48 weeks after treatment initiation were evaluated. Serological characteristics were also analysed and compared between the NA-PegIFNα combination therapy and NA monotherapy groups and between histological responders and nonresponders. Compared to baseline biopsies, both fibrosis staging and necroinflammatory grading scores were significantly lower in the second biopsies examined post-treatment in both groups. Nearly all patients experienced a reduction in inflammation (87.5% in both groups), but there was a subgroup of patients who exhibited either no significant improvement or fibrosis progression (33.3% and 31.2% in the NA monotherapy and NA-PegIFNα combination therapy groups, respectively). Nearly, all patients achieved ALT normalization and sustained virological response (SVR) after 48 weeks of antiviral treatment. Approximately one-third of individuals (36.8% and 30% in the two groups, respectively) achieved HBeAg loss at 48 weeks after treatment initiation. Although there were no significant differences in overall rates of histological, biochemical, virological and serological responses between the two groups, an earlier virological response and a higher cumulative SVR rate over time were observed during long-term follow-up in patients treated with NA-PegIFNα combination therapy (P = 0.0129). Trends of more rapid HBeAg loss and a higher cumulative HBeAg loss rate throughout long-term follow-up were also observed but were not statistically significant. The ALT normalization rates at 24 and 48 weeks after treatment initiation were associated with the histological response. Significant regression of fibrosis and resolution of necroinflammation were induced with either NA-PegIFNα combination therapy or NA monotherapy. Significant biochemical, virological and serological responses were observed in both groups, and the response rates at 48 weeks were similar in the two groups. Over time during long-term follow-up, the virological and serological responses were faster and superior following the combination regimen.
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Affiliation(s)
- Qiran Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Guojun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Yiqi Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
| | - Jianming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhangzhang Song
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Yusheng Yang
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Xinfang Du
- Department of Hepatology, Beilun People's Hospital, Ningbo, China
| | - Jiemin Hong
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Niuniu Li
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Quanzhen Tang
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Long Xu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Xuanyi Wang
- Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
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Lee JI, Lee HW, Kim SU, Ahn SH, Lee KS. Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis. Cancers (Basel) 2019; 11:425. [PMID: 30934621 PMCID: PMC6468874 DOI: 10.3390/cancers11030425] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/19/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023] Open
Abstract
The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0⁻A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307⁻0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296⁻8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396⁻7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086⁻0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086⁻0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566⁻24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188⁻8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.
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Affiliation(s)
- Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
- Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea.
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
- Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea.
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
- Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
- Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
- Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea.
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40
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Correlation of serum Mac-2-binding protein glycosylation isomer (M2BPGi) and liver stiffness in chronic hepatitis B infection. Hepatol Int 2019; 13:148-156. [PMID: 30671807 DOI: 10.1007/s12072-019-09928-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 01/07/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel serum diagnostic marker for liver fibrosis in various liver diseases. We aimed to evaluate its role in assessment of liver fibrosis in chronic hepatitis B infection (CHB) with reference to liver stiffness measurement (LSM). METHODS CHB patients with LSM by transient elastography technology and retrievable serum samples were recruited. Ten-year re-assessments of LSM and M2BPGi were repeated in a patient subgroup. RESULTS 240 CHB patients (M:F = 116:124; median age 47.5 years) were recruited. The median M2BPGi values for F0/F1/F2, F3 and F4 progressively increased with more advanced stages of liver fibrosis: 0.39, 0.46 and 0.82 COI, respectively (p < 0.01). M2BPGi levels correlated well with liver stiffness (r = 0.611), FIB-4 (r = 0.616), and strongly with APRI (r = 0.825) (all p < 0.001). Using cut-off values of 0.605 and 0.615 COI, the AUROCs were 0.754 and 0.799 for ≥ F3 and F4, respectively. M2BPGi identified one-quarter patients at risk of advanced fibrosis/cirrhosis otherwise classified into 'grey area' by LSM. In 86 patients with reassessment LSM, 21 (24.4%) showed significant fibrosis regression with corresponding decline in median M2BPGi level (- 0.11 COI) compared with the increase of +0.03 COI in patients without significant fibrosis regression (p = 0.011). Male gender, older age, use of potent antiviral therapy and change in serum M2BPGi were independently associated with significant fibrosis regression. CONCLUSIONS Serum M2BPGi can risk-stratify CHB patients whose liver stiffness fell into the 'grey area'. Significant fibrosis regression occurring in one-quarter patients was reflected by a reduction in M2BPGi levels at 10-year interval.
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Kostyusheva A, Kostyushev D, Brezgin S, Volchkova E, Chulanov V. Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure. Genes (Basel) 2018; 9:E483. [PMID: 30301171 PMCID: PMC6210151 DOI: 10.3390/genes9100483] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/30/2018] [Accepted: 10/03/2018] [Indexed: 12/12/2022] Open
Abstract
. Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.
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Affiliation(s)
| | | | - Sergey Brezgin
- Central Research Institute of Epidemiology, Moscow, 111123, Russia.
- National Research Centre, Institute of Immunology, Federal Medical Biological Agency, Moscow, 115478, Russia.
| | - Elena Volchkova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119146, Russia.
| | - Vladimir Chulanov
- Central Research Institute of Epidemiology, Moscow, 111123, Russia.
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, 119146, Russia.
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42
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Facciorusso A, Garcia Perdomo HA, Muscatiello N, Buccino RV, Wong VWS, Singh S. Systematic review with meta-analysis: Change in liver stiffness during anti-viral therapy in patients with hepatitis B. Dig Liver Dis 2018; 50:787-794. [PMID: 29807871 DOI: 10.1016/j.dld.2018.05.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 04/27/2018] [Accepted: 05/05/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Time-varying impact of anti-viral therapy on liver stiffness in patients with hepatitis B is unclear. AIMS To estimate the magnitude and kinetics of change in liver stiffness in hepatitis B patients treated with nucleot(s)ide analogs. METHODS Through a systematic review of multiple databases, we identified 24 studies in adults with hepatitis B who underwent transient elastography before and at least 6 months after starting nucleot(s)ide analogs therapy. We estimated change in liver stiffness 6 m, 12 m, 24 m, 36 m and 60 m after starting therapy, as weighted mean difference and 95% confidence intervals, using random-effects meta-analysis. RESULTS Liver stiffness significantly declined by 2.21 kPa (95% CI, -1.36 to -3.05), 2.56 kPa (-2.23 to -2.89), 3.73 kPa (-2.98 to -4.49), 4.15 kPa (-2.75 to -5.54), and 5.19 kPa (-3.34 to -7.03) at 6 months, 1 year, 2 years, 3 years, and 5 years from the start of therapy, respectively (p < 0.001). High baseline alanine aminotransferase level, viral load and liver stiffness were associated with greater magnitude of decline in liver stiffness. CONCLUSIONS Antiviral therapy is associated with progressive decline in liver stiffness in patients with hepatitis B, particularly in patients with high baseline alanine aminotransferase and viral load.
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Affiliation(s)
- Antonio Facciorusso
- Gastroenterology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy.
| | | | - Nicola Muscatiello
- Gastroenterology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy
| | | | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, United States; Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, United States
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43
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Mak LY, Wong DKH, Cheung KS, Seto WK, Lai CL, Yuen MF. Role of serum M2BPGi levels on diagnosing significant liver fibrosis and cirrhosis in treated patients with chronic hepatitis B virus infection. Clin Transl Gastroenterol 2018; 9:163. [PMID: 29915243 PMCID: PMC6006340 DOI: 10.1038/s41424-018-0020-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/26/2018] [Accepted: 03/12/2018] [Indexed: 12/16/2022] Open
Abstract
Background Mac-2-binding protein glycosylation isomer (M2BPGi), a novel serum marker for liver fibrosis, was seldom studied in chronic hepatitis B (CHB). We aimed to evaluate its role on diagnosing significant fibrosis and cirrhosis in treated CHB patients. Methods CHB patients treated with nucleos(t)ide analogues (NAs) with baseline liver biopsies and retrievable serum samples were recruited. Paired liver biopsies were performed in patient subgroups at 1 and 3 years. Results In total, 327 NA-treated CHB patients (M:F = 229:98; median age 38.1 years) were recruited. The median M2BPGi values were 0.26, 0.34, 0.57 and 1.21 cutoff index (COI), in liver histology with Ishak F0–1, F2, F3 and F4, respectively (p < 0.01). M2BPGi levels correlated with the Ishak scores (ρ = 0.312, p < 0.001). Using the cutoff values of 0.25, 0.45 and 0.96 COI for ≥F2, ≥F3 and F4, the AUROCs were 0.653, 0.795 and 0.914, respectively. Multivariate analysis with several other serum indices showed that M2BPGi was the most significant independent factor for ≥F3 (OR: 8.197, 95% CI: 2.699–24.897, p < 0.001). In patient subgroups with serial liver biopsies, both the proportion of F3/F4 and M2BPGi decreased at 1 year (8.3% vs. 2.8% and 0.32 vs. 0.21 COI, respectively; both p < 0.001). Histological fibrosis progression after ≥3 years of NA therapy accompanied with an increase in M2BPGi level, compared to patients without progression (+0.14 vs −0.03 COI, p = 0.045). Conclusion Serum M2BPGi is a reliable non-invasive marker for diagnosing ≥F2, ≥F3 and F4. It is the only significant marker for ≥F3 among several other indices. NA produced concordant dynamic changes in M2BPGi levels and histological fibrosis.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ka-Shing Cheung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ching-Lung Lai
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. .,State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
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44
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Ebrahimi H, Naderian M, Sohrabpour AA. New Concepts on Reversibility and Targeting of Liver Fibrosis; A Review Article. Middle East J Dig Dis 2018; 10:133-148. [PMID: 30186577 PMCID: PMC6119836 DOI: 10.15171/mejdd.2018.103] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
Currently, liver fibrosis and its complications are regarded as critical health problems.
With the studies showing the reversible nature of liver fibrogenesis, scientists have focused
on understanding the underlying mechanism of this condition in order to develop new
therapeutic strategies. Although hepatic stellate cells are known as the primary cells
responsible for liver fibrogenesis, studies have shown contributing roles for other cells,
pathways, and molecules in the development of fibrosis depending on the etiology of
liver fibrosis. Hence, interventions could be directed in the proper way for each type of
liver diseases to better address this complication. There are two main approaches in clinical
reversion of liver fibrosis; eliminating the underlying insult and targeting the fibrosis
process, which have variable clinical importance in the treatment of this disease. In this
review, we present recent concepts in molecular pathways of liver fibrosis reversibility
and their clinical implications.
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Affiliation(s)
- Hedyeh Ebrahimi
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Naderian
- The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- Associate Professor, The Liver, Pancreatic, and Biliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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45
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Wang Y, Liang X, Yang J, Wang H, Tan D, Chen S, Cheng J, Chen Y, Sun J, Rong F, Yang W, Liu H, Liu Z, Zheng Y, Liang J, Li S, Liu Z, Hou J. Improved performance of quantitative collagen parameters versus standard histology in longitudinal assessment of nonadvanced liver fibrosis for chronic hepatitis B. J Viral Hepat 2018; 25:598-607. [PMID: 29193542 DOI: 10.1111/jvh.12835] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Accepted: 10/09/2017] [Indexed: 12/13/2022]
Abstract
Monitoring longitudinal nonadvanced fibrosis is a more common scenario in management of chronic hepatitis B (CHB), for which, however, current evaluation methods generally lack sufficient performance. We conducted a proof-of-concept study to evaluate the performance of quantitative fibrous collagen parameters (q-FP) in the assessment. Data sets from a prior CHB trial (NCT00962533) with mostly mild-to-moderate fibrosis participants were used for this study. 301 subjects with paired liver biopsies were consecutively included. Of these, 139 subjects were used to establish the test and the rest for internal validation. Fibrosis change between baseline and week 104 of treatment was blindly assessed with q-FP and was compared with Ishak fibrosis staging. There were 70% and 93% subjects with Ishak F0-2 at baseline and week 104, respectively. For the test of the subjects, q-FP and Ishak staging showed no difference in determining the incidence of fibrosis regression (68% vs 67%; difference = 0.7%, P = 1.00). Q-FP demonstrated that the regression was independently associated with the antiviral efficacy endpoint (OR 3.0, 95% CI 1.4-6.5, P = .005), but Ishak failed the detection (OR 0.6, 95% CI 0.3-1.3, P = .24). Moreover, q-FP directly revealed a higher fibrosis-resistance to antiviral treatment in virus genotypes C vs B and in males vs females. These results were confirmed in the validation subjects. Additionally, a functional model built on the test subjects showed an accuracy of 82% in stratifying fibrosis reversibility of the validation subjects. In conclusion, q-FP could have improved efficiency and accuracy in the longitudinal assessment of mild-to-moderate CHB fibrosis, indicating a potential alternative to current evaluation methodologies.
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Affiliation(s)
- Y Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - X Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - J Yang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - H Wang
- Hepatology Unit, Peking University People's Hospital, Beijing, China
| | - D Tan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - S Chen
- Shandong Province Liver Disease Diagnosis and Treatment Center, Ji'nan Infectious Disease Hospital, Ji'nan, China
| | - J Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Y Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - J Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - F Rong
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - W Yang
- Guangdong Provincial Key Laboratory of Medical Image Processing, School of Biomedical Engineering, Southern Medical University, Guangzhou, China
| | - H Liu
- The Second School of Medicine, Southern Medical University, Guangzhou, China
| | - Z Liu
- The Second School of Medicine, Southern Medical University, Guangzhou, China
| | - Y Zheng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - J Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - S Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Biomedical Research Center, Southern Medical University, Guangzhou, China
| | - Z Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - J Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Guangdong Provincial Research Center for Liver Fibrosis, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Wang Q, Li H, Ding D, Peng M, Ren H, Hu P. Upgrade Combination Response Is Limited by Prolonged Nucelos(t)ide Analogue Therapy in HBeAg-positive Chronic Hepatitis B: A Real-life Study. J Clin Transl Hepatol 2018; 6:11-17. [PMID: 29577027 PMCID: PMC5862994 DOI: 10.14218/jcth.2017.00020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 08/04/2017] [Accepted: 08/21/2017] [Indexed: 12/16/2022] Open
Abstract
Background and Aims: Few previous studies have reported on a combination response (hepatitis B virus (HBV) DNA undetected, alanine aminotransferase normalization and hepatitis B e antigen (HBeAg) seroconversion) following nucleos(t)ide analogue (NAs) long-term therapy in patients with chronic hepatitis B (CHB). This study aimed to investigate the combination response on long-term NAs therapy in patients with HBeAg-positive CHB and to determine whether prolonged therapy is beneficial for combination response, particularly in optimal patients (baseline alanine aminotransferase level ≥5 upper limit of normal and HBV DNA level <109 copies/mL). Methods: In total, 280 HBeAg-positive CHB patients were enrolled in this study. Among them, 190 were treated with entecavir and 90 were treated with telbivudine. Results: The cumulative rates of combination response in the total number of patients were 8.6% at 1 year, 13.2% at 2 years, 19.1% at 3 years, 24.2% at 4 years and 26.0% at 5 years. In optimal patients, the cumulative rate of combination response was significantly higher than that in the non-optimal patients at 3 years (p = 0.043); the trend of the cumulative rate was not strong at the later time. Interestingly, in optimal patients, combination response mainly occurred in the first 3 years. Multivariate analysis identified HBeAg/anti-HBe seroconversion at 1 year as the only factor for combination response in optimal patients (hazard ratio: 16.321; p = 0.000). During the 3 years, the proportion with aspartate aminotransaminase to platelet ratio index ≤0.5 increased from 15.6% at baseline to 71.3% at year 3. Conclusions: Upgrading the rate of combination response is limited by prolonging the treatment duration of NAs from 3 years to 5 years in HBeAg-positive CHB patients; a new switch treatment strategy modification should be considered, particularly in optimal patients.
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Affiliation(s)
- Qiaohe Wang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Disease, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hu Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Disease, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Daohai Ding
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Disease, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Disease, 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 Disease, 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 Disease, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence to: Peng Hu, Department of Infectious Diseases, Institute for Viral Hepatitis, 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. Tel: +86-23-63693289, Fax: +86-23-63703790, E-mail:
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47
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Rinaldi L, Ascione A, Messina V, Rosato V, Valente G, Sangiovanni V, Zampino R, Marrone A, Fontanella L, de Rosa N, Orabona P, Buonomo C, Chirianni A, Adinolfi LE, Piai G. Influence of antiviral therapy on the liver stiffness in chronic HBV hepatitis. Infection 2018; 46:231-238. [PMID: 29335905 DOI: 10.1007/s15010-017-1113-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 12/29/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE The aim of this study was to evaluate the effects of antiviral therapy on liver stiffness measurement (LSM). METHODS Two hundred HBV patients were enrolled from four hospital centers in southern Italy; median age was 50.7 (25-75) males were 68%; 171 patients underwent to liver biopsy and 200 patients had LSM at baseline and 189 at the end of follow-up. One hundred and forty-nine patients were treated with nucleos(t)ide analogs, while 51 patients were untreated. The cutoffs of the LSM, related to the fibrosis stages, were as follows: non-advanced fibrosis ≤ 8.1 kPa and advanced fibrosis ≥ 8.2 Kpa. RESULTS At baseline, the median value of LSM was 14.1 kPa for advanced fibrosis/cirrhosis and 6.9 kPa for non-advanced fibrosis. LSM was performed at 24 months from the start of therapy. The treated patients (68% received Entecavir and 32% Tenofovir) showed a decrease in liver stiffness measurement of 1.5 kPa (p < 0.001) in non-advanced fibrosis and of 6 kPa (p < 0.001) in advanced fibrosis/cirrhosis. In the patients not undergoing antiviral treatment, no statistically significant change of the LSM was observed (p = 0.26). A logistic binary regression model showed that the only independent factor associated with a significant change in the LSM was the liver stiffness value at baseline (odd ratio 2.855; 95% CI 1.456-5.788; (p = 0.007). CONCLUSION Long-term antiviral therapy induced a significant reduction of liver stiffness measurement and this result may be related to the reduction of liver fibrosis.
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Affiliation(s)
- Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 80138, Naples, Italy.
| | - Antonio Ascione
- Department of Internal Medicine, Centre for Liver Diseases, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy
| | - Vincenzo Messina
- Infectious Diseases C.O. Unit, AORN S. Anna and S. Sebastiano, Caserta, Italy
| | - Valerio Rosato
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 80138, Naples, Italy
| | - Giovanna Valente
- Department of Medical Sciences, AORN S.Anna e S. Sebastiano, Caserta, Italy
| | - Vincenzo Sangiovanni
- Department of Infectious Emergencies and Infectious Diseases, Azienda Ospedaliera Dei Colli, Naples, Italy
| | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 80138, Naples, Italy
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 80138, Naples, Italy
| | - Luca Fontanella
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 80138, Naples, Italy
| | - Nicolina de Rosa
- Department of Diagnostic Service, Azienda Ospedaliera dei Colli, Naples, Italy
| | - Pasquale Orabona
- Department of Service, AORN S. Anna and S. Sebastiano, Caserta, Italy
| | - Carmela Buonomo
- Department of Service, AORN S. Anna and S. Sebastiano, Caserta, Italy
| | - Antonio Chirianni
- Department of Infectious Emergencies and Infectious Diseases, Azienda Ospedaliera Dei Colli, Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 80138, Naples, Italy
| | - Guido Piai
- Department of Medical Sciences, AORN S.Anna e S. Sebastiano, Caserta, Italy
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48
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Mgaieth S, Kemp W, Gow P, Fink M, Lubel J, Nicoll A, Gazzola A, Hong T, Ryan M, Knight V, Dev AT, Sood S, Bell S, Paul E, Roberts SK. Impact of viral hepatitis aetiology on survival outcomes in hepatocellular carcinoma: A large multicentre cohort study. J Viral Hepat 2017; 24:982-989. [PMID: 28414893 DOI: 10.1111/jvh.12717] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 02/27/2017] [Indexed: 12/15/2022]
Abstract
While HBV and HCV are risk factors for HCC, uncertainty exists as to whether these viral infections have prognostic significance in HCC. Thus, we compared the overall survival of patients with HBV, HCV and nonviral HCC, and evaluated whether the presence of HBV and HCV predicts patient outcomes. We conducted a multicentre study of HCC cases diagnosed at six Melbourne tertiary hospitals between Jan 2000-Dec 2014. Patient demographics, liver disease and tumour characteristics and patient outcomes were obtained from hospital databases, computer records and the Victorian Death Registry. Survival outcomes were compared between HBV, HCV and nonviral hepatitis cases and predictors of survival determined using Cox proportional hazards regression. There were 1436 new HCC cases identified including 776 due to viral hepatitis (HBV 235, HCV 511, HBV-HCV 30) and 660 from nonviral causes. The median survival of HBV, HCV and nonviral HCC patients was 59.1, 28.4 and 20.9 months, respectively (P<.0001). On multivariate analysis, independent risk factors for survival included HCC aetiology, gender, BCLC stage, serum AFP, total number and size of lesions, and serum creatinine and albumin. After adjusting for these and method of detection, HBV remained an independent predictor of improved overall survival when compared to both nonviral (HR 0.60%, 95% CI 0.35-0.98; P=.03) and HCV-related HCC (HR 0.51%, 95% CI 0.30-0.85; P=.01). In this large multicentre study, HBV is independently associated with improved overall survival compared with HCV and nonviral-related HCC. Further studies are needed to determine the underlying factor(s) responsible.
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Affiliation(s)
- S Mgaieth
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - W Kemp
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - P Gow
- Department of Gastroenterology, Austin Hospital, Heidelberg, Vic., Australia
| | - M Fink
- Department of Surgery, Austin Hospital, Heidelberg, Vic., Australia
| | - J Lubel
- Department of Gastroenterology, Box Hill Hospital, Box Hill, Vic., Australia
| | - A Nicoll
- Department of Gastroenterology, Box Hill Hospital, Box Hill, Vic., Australia.,Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Vic., Australia
| | - A Gazzola
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - T Hong
- Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Vic., Australia
| | - M Ryan
- Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Vic., Australia
| | - V Knight
- Department of Gastroenterology, Monash Medical Centre, Clayton, Vic., Australia
| | - A T Dev
- Department of Gastroenterology, Monash Medical Centre, Clayton, Vic., Australia
| | - S Sood
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Vic., Australia
| | - S Bell
- Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Vic., Australia
| | - E Paul
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia
| | - S K Roberts
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
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49
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Young K, Liu B, Bhuket T, Younossi Z, Saab S, Ahmed A, Wong RJ. Long-term trends in chronic hepatitis B virus infection associated liver transplantation outcomes in the United States. J Viral Hepat 2017; 24:789-796. [PMID: 28273387 DOI: 10.1111/jvh.12703] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 02/02/2017] [Indexed: 12/19/2022]
Abstract
With effective antiviral therapies, rates of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and decompensated liver disease requiring liver transplantation (LT) are expected to decrease. We aim to evaluate overall trends in LT waitlist registrations, waitlist survival and likelihood of receiving LT among chronic HBV patients in the United States. Using the United Network for Organ Sharing database, we retrospectively evaluated adults (age≥18) with chronic HBV (with and without HCC) listed for LT from 1992 to 1996 (Era 1) vs 1997 to 2004 (Era 2) vs 2005-2015 (Era 3). Multivariate Cox-regression models evaluated probability of waitlist survival and receiving LT. Overall, 6797 chronic HBV adults were listed for LT. While the total number of HBV patients listed for LT remained stable, the proportion of HBV patients with HCC increased from 5.4% in Era 1 to 39.0% in Era 3. Compared to Era 1, waitlist mortality was higher in Era 2 (HR: 4.55, P<.001) and Era 3 (HR: 3.63, P<.001). However, in the most recent era, waitlist mortality significantly improved (compared to 2005-2007: 2008-2011: HR: 0.74, P=.05, 95% CI: 0.55-0.99; 2012-2015: HR: 0.53, P<.001, 95% CI: 0.38-0.75). Probability of receiving LT was also lower with latter time periods (compared to 2005-2007: 2008-2011: HR: 0.77, P<.001 95% CI: 0.68-0.86; 2012-2015: HR: 0.61, P<.001, 95% CI: 0.54-0.69). Although the number of HBV patients requiring LT remained stable, the proportion of HBV patients with HCC continues to rise. The decrease in waitlist mortality and lower likelihood of LT among HBV patients may reflect the effectiveness of antiviral therapies in delaying disease progression in the current era.
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Affiliation(s)
- K Young
- Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA
| | - B Liu
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Oakland, CA, USA
| | - T Bhuket
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Oakland, CA, USA
| | - Z Younossi
- Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA.,Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
| | - S Saab
- Departments of Medicine and Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA
| | - A Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - R J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Oakland, CA, USA
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50
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Liver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with tenofovir disoproxil fumarate in France: a prospective cohort study. J Int AIDS Soc 2017; 20:21426. [PMID: 28362068 PMCID: PMC5467614 DOI: 10.7448/ias.20.1.21426] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Introduction: Long-term tenofovir disoproxil fumarate (TDF) use has been associated with significant regression of liver fibrosis during hepatitis B virus (HBV) mono-infection, yet little is known during HIV–HBV coinfection. The aim of this study was to evaluate the evolution of liver fibrosis and its determinants in TDF-treated coinfected patients. Methods: In this prospective cohort study, 167 HIV–HBV-infected patients initiating TDF-containing antiretroviral therapy were included. Fibrosis was assessed using the FibroTest® at baseline and every six to twelve months. Risk factors for fibrosis progression (F0–F1–F2 to F3–F4) and regression (F3–F4 to F0–F1–F2) were evaluated. Results: At baseline, 134 (80.2%) patients had detectable HBV-DNA (median = 4.93 log10 IU/mL, IQR = 2.94–7.15) and 104 (62.3%) had hepatitis B “e” antigen-positive serology. Median follow-up was sixty months (IQR = 36–93). In the 47 (28.1%) patients with F3–F4 baseline fibrosis, 7/47 (14.9%) regressed to F0–F1–F2 at last follow-up visit. Fibrosis regression was significantly associated with higher CD4+ cell counts (P = 0.009) and lower fasting triglyceride levels (P = 0.007) at TDF-initiation. In the 120 (71.9%) patients with F0–F1–F2-baseline fibrosis, 20/120 (16.7%) progressed to F3–F4 at last follow-up visit. Fibrosis progression was associated with male gender (P = 0.01), older age (P = 0.001), from low/moderate HBV-endemic country (P = 0.007), lower nadir CD4+ cell count (P = 0.03), higher fasting glycaemia (P = 0.03) and anaemia (P = 0.004) at TDF-initiation. Control of HBV replication at end of follow-up was extensive (88.1%), while no HBV-related factors emerged as predictors of progression/regression. Incidence of severe liver-related events was low (n = 4, rate = 0.5/100 person-years). Conclusions: Liver fibrosis levels are stable for most coinfected patients undergoing TDF, despite control of HBV replication. Nevertheless, a concerning amount of liver fibrosis progression did occur, which could be partly explained by metabolic abnormalities and past severe immunosuppression and requires further evaluation.
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