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Zhang Y, Xia H, Fan L, Jiang L, Yang B, Wang F. Five-Year Prospective Follow-Up of Patients with Hepatitis C Virus Infection Treated with Direct-Acting Antiviral Agents. Infect Drug Resist 2025; 18:455-471. [PMID: 39877380 PMCID: PMC11774102 DOI: 10.2147/idr.s487414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 01/11/2025] [Indexed: 01/31/2025] Open
Abstract
Purpose The research intended to present prospective data on the long-term prognosis of individuals with hepatitis C virus (HCV) infection who received direct-acting antiviral agent (DAA) treatment. Patients and Methods Patients who received DAA treatment at Tianjin Third Central Hospital and Tianjin Second People's Hospital were prospectively enrolled and subsequently underwent a longitudinal follow-up. This research monitored occurrences of virological relapse, hepatocellular carcinoma (HCC), mortality, and liver disease progression. The annualized incidence rates (AIRs), cumulative incidence rates of adverse events and risk factors were investigated. Changes in liver stiffness measurement (LSM), aspartate aminotransferase-to-platelet ratio index (APRI) score, fibrosis-4 (FIB-4) index, as well as the albumin-bilirubin (ALBI) scores were also documented. Results A total of 862 individuals were followed up for 4.86 (P25, P75; 4.48, 5.48) years. The proportion of all participants with undetectable HCV-RNA exceeded 98% at all follow-up time points. Patients experienced virological relapse, HCC, death and disease progression with a cumulative AIRs of 1.03% (95% confidence interval [CI] 0.6-1.5), 1.76% (95% CI 1.2-2.3), 1.51% (95% CI 1.0-2.0), and 5.81% (95% CI 4.8-6.8), respectively. Cirrhotic patients were at a heightened risk of virological relapse (adjusted hazard ratio [aHR] 3.20, 95% CI 1.59-9.75; p = 0.016), HCC (aHR 6.57, 95% CI 2.66-16.28; p < 0.0001), and unfavorable prognosis (aHR 6.93, 95% CI 2.56-18.74; p < 0.0001). Additionally, patients with diabetes faced an elevated risk of HCC (aHR 2.33, 95% CI 1.05-5.15; p = 0.038) and poor prognosis (aHR 2.72, 95% CI 1.13-6.55; p = 0.026). Furthermore, liver stiffness measurement (LSM) exhibited a significant decrease compared to baseline. Additionally, patients in the cirrhosis group showed reductions in APRI score, FIB-4 index and ALBI score to different degrees. Conclusion Cirrhotic patients exhibited increased susceptibility to virological relapse, HCC, unfavorable prognosis, and liver disease progression following DAA treatment. Consequently, it is imperative to implement a rigorous monitoring protocol for all cirrhotic patients after DAA treatment.
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Affiliation(s)
- Yaping Zhang
- The Third Central Clinical College of Tianjin Medical University, Tianjin Medical University, Tianjin, 300170, People’s Republic of China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated Third Central Hospital, Tianjin, 300072, People’s Republic of China
| | - Huan Xia
- Department of Infectious Diseases, Tianjin Second People’s Hospital, Tianjin, 300192, People’s Republic of China
| | - Luchang Fan
- The Third Central Clinical College of Tianjin Medical University, Tianjin Medical University, Tianjin, 300170, People’s Republic of China
| | - Lu Jiang
- Department of Hepatology and Gastroenterology, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China
| | - Bin Yang
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated Third Central Hospital, Tianjin, 300072, People’s Republic of China
| | - Fengmei Wang
- Department of Hepatology and Gastroenterology, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China
- Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Central Hospitial, Tianjin, 300192, People’s Republic of China
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Ye YM, Lin Y, Sun F, Yang WY, Zhou L, Lin C, Pan C. A predictive model for functional cure in chronic HBV patients treated with pegylated interferon alpha: a comparative study of multiple algorithms based on clinical data. Virol J 2024; 21:333. [PMID: 39710712 PMCID: PMC11665216 DOI: 10.1186/s12985-024-02599-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/04/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND A multivariate predictive model was constructed using baseline and 12-week clinical data to evaluate the rate of clearance of hepatitis B surface antigen (HBsAg) at the 48-week mark in patients diagnosed with chronic hepatitis B who are receiving treatment with pegylated interferon α (PEG-INFα). METHODS The study cohort comprised CHB patients who received pegylated interferon treatment at Mengchao Hepatobiliary Hospital, Fujian Medical University, between January 2019 and April 2024. Predictor variables were identified (LASSO), followed by multivariate analysis and logistic regression analysis. Subsequently, predictive models were developed via logistic regression, random forest (RF), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and support vector machine (SVM) algorithms. The efficacy of these models was assessed through various performance metrics, including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and F1 score. RESULTS This study included a total of 224 individuals diagnosed with chronic hepatitis B. The variables baseline log2(HBsAg), gender, age, neutrophil count at week 12, HBsAg decline rate at week 12, and HBcAb at week 12 were closely associated with functional cure and were included in the predictive model. In the validation term, the logistic regression model had an AUC of 0.858, which was better than that of the other machine learning models (AUC = 0.858,F1 = 0.753). Consequently, this model was selected for the development of the predictive tool. CONCLUSIONS The combined use of the baseline log2(HBsAg) value, HBsAg decline rate at week 12, gender, neutrophil count at week 12, and age can serve as a foundational predicting model for anticipating the clearance of HBsAg in individuals with chronic hepatitis B who are receiving PEG-INFα therapy.
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Affiliation(s)
- Ya-Mei Ye
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China
| | - Yong Lin
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China
| | - Fang Sun
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China
| | - Wen-Yan Yang
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China
| | - Lina Zhou
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China
| | - Chun Lin
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China.
| | - Chen Pan
- Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China.
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Fiduzi FIF, Willemssen FEJA, de Braak CV, de Lussanet de la Sablonière QG, IJzermans JNM, Bos D, de Man RA, Dwarkasing RS. Evaluation of Hepatocellular Carcinoma Surveillance with Contrast-enhanced MRI in a High-Risk Western European Cohort. Curr Probl Diagn Radiol 2024; 53:709-716. [PMID: 39003123 DOI: 10.1067/j.cpradiol.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/04/2024] [Accepted: 07/08/2024] [Indexed: 07/15/2024]
Abstract
AIM To investigate the utilization of MRI using a MRI liver protocol with extracellular contrast-enhanced series for hepatocellular carcinoma (HCC) surveillance in high-risk patients. METHODS Consecutive high-risk patients of a western European cohort who underwent repeated liver MRI for HCC screening were included. Lesions were registered according to the Liver Reporting & Data System (LIRADS) 2018. HCC was staged as very early stage HCC (BCLC stage 0) and more advanced stages of HCC (BCLC stage A-D). Differences in time interval between MRI's for BCLC stage 0 and stage A-D were calculated with the Mann-Whitney U test. The HCC cumulative incidence at one-, three- and five years was calculated with the Kaplan Meier estimator. RESULTS From 2010 to 2019 a total of 240 patients were included (71% male; median age: 57 years; IQR: 50-64 years) with 1350 MRI's. Most patients (83 %) had cirrhosis with hepatitis C as the most common underlying cause. Patients underwent on average four MRI's (IQR: 3-7). Forty-two patients (17.5%) developed HCC (52 HCC lesions: 43 LIRADS-5, eight LIRADS-4, and one LIRADS-TIV). Eighteen patients (43%) had BCLC stage 0 HCC with a significant shorter screening time interval (10 months; IQR: 6-21) compared to patients with BCLC stage A-D (21 months; IQR: 10-32) (p = 0.03). Thirty seven percent of patients with a LIRADS-3 lesion (n=43) showed HCC development within twelve months (median: 7.4 months). One, three- and five-year HCC cumulative incidence in cirrhotic patients was 1%, 10% and 17%, respectively. CONCLUSION High-risk patients who underwent surveillance with contrast-enhanced MRI developed HCC in 17.5 % during a follow up period of over 4 years median. Very early stage HCC was seen in compensated cirrhosis after a median time interval of 10 months. Later stages of HCC were related to prolonged screening time interval (median 21 months).
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Affiliation(s)
- Federico I F Fiduzi
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | - François E J A Willemssen
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | - Céline van de Braak
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | | | - Jan N M IJzermans
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Daniel Bos
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Robert A de Man
- Department of Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Roy S Dwarkasing
- Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands.
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Wang X, Lin ZY, Zhou Y, Zhong Q, Li ZR, Lin XX, Hu MG, He KL. Association of preoperative antiviral treatment with incidences of post-hepatectomy liver failure in hepatitis B virus-related hepatocellular carcinoma. World J Gastrointest Surg 2024; 16:2106-2118. [PMID: 39087126 PMCID: PMC11287710 DOI: 10.4240/wjgs.v16.i7.2106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/03/2024] [Accepted: 06/20/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is a common consequence of radical partial hepatectomy in hepatocellular carcinoma (HCC). AIMS To investigate the relationship between preoperative antiviral therapy and PHLF, as well as assess the potential efficacy of hepatitis B virus (HBV) DNA level in predicting PHLF. METHODS A retrospective study was performed involving 1301 HCC patients with HBV who underwent radical hepatectomy. Receiver operating characteristic (ROC) analysis was used to assess the capacity of HBV DNA to predict PHLF and establish the optimal cutoff value for subsequent analyses. Logistic regression analyses were performed to assess the independent risk factors of PHLF. The increase in the area under the ROC curve, categorical net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to quantify the efficacy of HBV DNA level for predicting PHLF. The P < 0.05 was considered statistically significant. RESULTS Logistic regression analyses showed that preoperative antiviral therapy was independently associated with a reduced risk of PHLF (P < 0.05). HBV DNA level with an optimal cutoff value of 269 IU/mL (P < 0.001) was an independent risk factor of PHLF. All the reference models by adding the variable of HBV DNA level had an improvement in area under the curve, categorical NRI, and IDI, particularly for the fibrosis-4 model, with values of 0.729 (95%CI: 0.705-0.754), 1.382 (95%CI: 1.341-1.423), and 0.112 (95%CI: 0.110-0.114), respectively. All the above findings were statistically significant. CONCLUSION In summary, preoperative antiviral treatment can reduce the incidence of PHLF, whereas an increased preoperative HBV DNA level has a correlative relationship with an increased susceptibility to PHLF.
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Affiliation(s)
- Xiao Wang
- Medical Big Data Research Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Hepatobiliary Surgery, Chinese PLA 970th Hospital, Yantai 264001, Shandong Province, China
| | - Zhao-Yi Lin
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - You Zhou
- Medical Big Data Research Center, Chinese PLA General Hospital, Beijing 100853, China
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Qin Zhong
- Medical Big Data Research Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
| | - Zong-Ren Li
- Medical Big Data Research Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
| | - Xi-Xiang Lin
- Medical Big Data Research Center, Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
| | - Ming-Gen Hu
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Kun-Lun He
- Medical Big Data Research Center, Chinese PLA General Hospital, Beijing 100853, China
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Shojaeian A, Nakhaie M, Amjad ZS, Boroujeni AK, Shokri S, Mahmoudvand S. Leveraging metformin to combat hepatocellular carcinoma: its therapeutic promise against hepatitis viral infections. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2023.147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis ), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
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Kudaravalli S, Kam LY, Huang DQ, Cheung R, Nguyen MH. Utilization of Antiviral Therapy for Patients With Hepatitis B-Related Hepatocellular Carcinoma: A Nationwide Real-World US Study. Clin Gastroenterol Hepatol 2023; 21:3305-3313.e4. [PMID: 37805836 DOI: 10.1016/j.cgh.2023.04.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/01/2023] [Accepted: 04/17/2023] [Indexed: 10/09/2023]
Abstract
BACKGROUND & AIMS Although oral antiviral therapy (OAV) is reported to improve outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), it is underutilized. We determined the rate and factors associated with OAV utilization among patients with HBV-related HCC in a US population with health insurance. METHODS Patients with HBV-related HCC were identified from the de-identified administrative health claims database for patients with private insurance, Optum Clinformatics (2003-2021). RESULTS We identified 2129 patients with HBV-related HCC: 71% male, mean age 62.7 ± 12.5 years, 40% Asian individuals, 72% with cirrhosis, and 37% received OAV. The treatment rate improved over time (40.5% after 2010 vs 26.3% earlier; P < .001). Significantly lower treatment rates were noted for females, non-Asian patients, noncirrhotic patients, and patients without gastroenterologist/hepatologist or infectious disease (GI/ID) specialist care (P < .0001). OAV treatment predictors included Asian race and ethnicity (adjusted odds ratio [aOR], 3.6; 95% CI, 2.8-4.5; P < .001), male sex (aOR, 1.6; 95% CI, 1.3-2.0; P < .001), seeing a GI/ID specialist (aOR, 1.5; 95% CI, 1.10-1.99; P = .0091), having compensated cirrhosis (aOR, 2.2; 95% CI, 1.7-2.8; P < .001), and being treated from 2011 to 2021 (aOR, 2.3; 95% CI, 1.8-3.0; P < .001); being younger (aOR, 0.98; 95% CI, 0.98-0.99; P < .001) was less likely for treatment. OAV initiated at or before HCC diagnosis was associated independently with improved survival (adjusted hazard ratio, 0.84; 95% CI, 0.72-0.99; P = .037). CONCLUSIONS Among patients with HBV-related HCC, only 1 in 3 received OAV despite having insurance coverage. Efforts must continue to develop ways to improve HBV OAV treatment, especially among females, non-Asian patients, and patients without cirrhosis or not seen by specialists.
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Affiliation(s)
- Sahith Kudaravalli
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Trinity College of Arts and Sciences, Duke University, Durham, North Carolina
| | - Leslie Y Kam
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
| | - Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University School of Medicine, Palo Alto, California.
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Lee CH, Lee YB, Moon H, Chung JW, Cho EJ, Lee JH, Yu SJ, Kim YJ, Lee J, Yoon JH. Association between daily aspirin therapy and risk of hepatocellular carcinoma according to metabolic risk factor burden in non-cirrhotic patients with chronic hepatitis B. Aliment Pharmacol Ther 2023; 58:704-714. [PMID: 37461332 DOI: 10.1111/apt.17643] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/22/2023] [Accepted: 07/04/2023] [Indexed: 07/20/2023]
Abstract
BACKGROUND Several studies have demonstrated chemopreventive effects of aspirin against hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). AIMS To investigate the associations of aspirin use with risks of HCC, liver-related mortality, and major bleeding according to metabolic risk factor burden among non-cirrhotic patients with CHB METHODS: Using the Korean National Health Insurance Service database, we identified 282,611 non-cirrhotic adults with CHB. Data on obesity, diabetes, high blood pressure, and hypercholesterolemia were collected. Subjects were stratified into lower and higher metabolic risk groups (≤2 and ≥3 risk factors, respectively). Propensity score-matched cohorts of aspirin users and non-users were generated. Risks of HCC, liver-related death and major bleeding were analyzed. RESULTS During the median follow-up of 7.4 years, positive associations between metabolic risk factor burden and outcomes were verified (all ptrend < 0.001). In the lower metabolic risk group (13,104 pairs), the association between aspirin use and HCC risk was not significant after multivariable adjustment (adjusted subdistribution hazard ratio [aSHR]: 0.93; 95% CI: 0.84-1.03); however, aspirin use was associated with elevated major bleeding risk (aSHR: 1.22; 95% CI: 1.08-1.39). In the higher metabolic risk group (2984 pairs), aspirin use was associated with reduced risks of HCC (aSHR: 0.72; 95% CI: 0.57-0.91) and liver-related mortality (aSHR: 0.69; 95% CI: 0.50-0.96) without an increase in risk of major bleeding (aSHR: 1.02; 95% CI: 0.79-1.32). CONCLUSIONS Aspirin therapy was associated with reduced risks of HCC and liver-related death without excess risk of major bleeding, in non-cirrhotic patients with CHB who had a higher metabolic risk factor burden.
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Affiliation(s)
- Cheol-Hyung Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyemi Moon
- Department of Biostatistics, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Jong-Won Chung
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Juneyoung Lee
- Department of Biostatistics, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Fang HW, Hu TH, Wang JH, Hung CH, Lu SN, Chen CH. Post-treatment HBsAg decline predicts high rate of HBsAg loss after stopping entecavir or tenofovir in HBeAg-negative patients without retreatment. Dig Liver Dis 2023; 55:1223-1229. [PMID: 36870864 DOI: 10.1016/j.dld.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/20/2023] [Accepted: 02/10/2023] [Indexed: 03/06/2023]
Abstract
BACKGROUND/AIMS Little is known about the role of post-treatment HBsAg decline in HBsAg loss following nucleos(t)ide analogues cessation. METHODS HBeAg-negative patients without cirrhosis who previously received entecavir or tenofovir disoproxil fumarate (TDF) were enrolled (n=530). All patients were followed-up post-treatment for >24 months. RESULTS Of the 530 patients, 126 achieved sustained response (Group I), 85 experienced virological relapse without clinical relapse and retreatment (Group II), 67 suffered clinical relapse without retreatment (Group III) and 252 received retreatment (Group IV). The cumulative incidence of HBsAg loss at 8 years was 57.3% in Group I, 24.1% in Group II, 35.9% in Group III and 7.3% in Group IV. Cox regression analysis showed that nucleos(t)ide analogue experience, lower HBsAg levels at end-of-treatment (EOT) and higher HBsAg decline at 6 months after EOT were independently associated with HBsAg loss in Group I and Groups II+III. The rates of HBsAg loss at 6 years in patients with HBsAg decline >0.2 log IU/mL in Group I and HBsAg decline >0.15 log IU/mL in Group II+III at 6 months after EOT were 87.7% and 47.1%, respectively. CONCLUSION The HBsAg loss rate was high and post-treatment HBsAg decline could predict high HBsAg loss rate among HBeAg-negative patients who discontinued entecavir or TDF and did not need retreatment.
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Affiliation(s)
- Hsin-Wei Fang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan, ROC.
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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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Tang Q, Ye J, Zhang Y, Zhang P, Xia G, Zhu J, Wei S, Li X, Zhang Z. Establishment of a multi-parameter prediction model for the functional cure of HBeAg-negative chronic hepatitis B patients treated with pegylated interferonα and decision process based on response-guided therapy strategy. BMC Infect Dis 2023; 23:456. [PMID: 37430256 PMCID: PMC10332036 DOI: 10.1186/s12879-023-08443-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 07/04/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND & AIMS This study aimed to establish multivariate prediction models according to a response-guided therapy (RGT) based strategy at baseline and week 12 and 24 of follow-up to predict the functional cure for HBeAg-negative patients with chronic hepatitis B (CHB) treated with pegylated interferonα (PEG-IFNα). METHODS A total of 242 HBeAg-negative patients with CHB were treated with PEG-IFNα for 52 weeks and followed up for 24 weeks. Responses at the end of follow-up (EOF) were defined as hepatitis B surface antigen (HBsAg) loss, and patients were defined as either responders or non-responders. RESULTS The three most meaningful predictors were an age ≤ 40 years, alanine aminotransferase (ALT) levels ≤ 40 U/L, and HBsAg levels ≤ 100 IU/mL at baseline; ALT levels ≥ 80 U/L, anti-HBc levels ≤ 8.42 S/CO, and HBsAg levels ≤ 50 IU/mL at week 12; and ALT levels ≥ 40 U/L, anti-HBc levels ≤ 8.46 S/CO, and HBsAg levels ≤ 0.2 IU/mL at week 24. The response rates of patients with a score of 0-1 and 4-5 at baseline, week 12, and 24 were 13.5%, 7.8%, and 11.7%; and 63.6%, 68.1%, and 98.1%, respectively. At week 12, the cumulative scores were 0-2, 3-4, 5-7, and 8-10 (response rates 5.0%, 18.9%, 41.3%, and 71.4%, respectively). At week 24, the cumulative scores were 0-3, 4-6, 7-10, and 11-15 (response rates: 1.3%, 12.3%, 37.0%, and 92.5%, respectively). At baseline, patients with scores of 0-1 were slightly recommended; at week 12, patients with 0-1 or 0-2 cumulative scores were recommended to stop treatment. At week 24, patients with a score of 0-1 or a cumulative score of 0-6 were recommended to stop treatment. CONCLUSION We established a multi-parameter prediction model for the functional cure of HBeAg-negative patients with CHB treated with PEG-IFNα.
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Affiliation(s)
- Qianqian Tang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Jun Ye
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Yafei Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Peixin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Guomei Xia
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Jie Zhu
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Shaofeng Wei
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xu Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China.
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Seong MS, Jang JA, Jeong YR, Kim YB, Kyaw YY, Kong HJ, Lee JH, Cheong J. Fibroblast Growth Factor 11 Inhibits Hepatitis B Virus Gene Expression Through FXRα Suppression. J Microbiol 2023; 61:693-702. [PMID: 37646922 PMCID: PMC10477102 DOI: 10.1007/s12275-023-00065-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 09/01/2023]
Abstract
Fibroblast growth factor 11 (FGF11) is a member of the intracellular FGF family, which shows different signal transmission compared with other FGF superfamily members. The molecular function of FGF11 is not clearly understood. In this study, we identified the inhibitory effect of FGF11 on hepatitis B virus (HBV) gene expression through transcriptional suppression. FGF11 decreased the mRNA and protein expression of HBV genes in liver cells. While the nuclear receptor FXRα1 increased HBV promoter transactivation, FGF11 decreased the FXRα-mediated gene induction of the HBV promoter by the FXRα agonist. Reduced endogenous levels of FXRα by siRNA and the dominant negative mutant protein (aa 1-187 without ligand binding domain) of FXRα expression indicated that HBV gene suppression by FGF11 is dependent on FXRα inhibition. In addition, FGF11 interacts with FXRα protein and reduces FXRα protein stability. These results indicate that FGF11 inhibits HBV replicative expression through the liver cell-specific transcription factor, FXRα, and suppresses HBV promoter activity. Our findings may contribute to the establishment of better regimens for the treatment of chronic HBV infections by including FGF11 to alter the bile acid mediated FXR pathway.
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Affiliation(s)
- Mi So Seong
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Jeong Ah Jang
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Ye Rim Jeong
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Ye Bin Kim
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea
| | - Yi Yi Kyaw
- Advanced Molecular Research Centre, Department of Medical Research, Republic of Union of Myanmar, Yangon, 11191, Myanmar
| | - Hee Jeong Kong
- Biotechnology Research Division, National Institute of Fisheries Science, Busan, 46083, Republic of Korea
| | - Jung-Hyun Lee
- Marine Biotechnology Research Center, Korea Institute of Ocean Science and Technology, Busan, 49111, Republic of Korea
| | - JaeHun Cheong
- Department of Molecular Biology, Pusan National University, Busan, 46241, Republic of Korea.
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12
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Wang Z, Wang X, Jin R, Liu F, Rao H, Wei L, Chen H, Feng B. LAMP3 expression in the liver is involved in T cell activation and adaptive immune regulation in hepatitis B virus infection. Front Immunol 2023; 14:1127572. [PMID: 37006307 PMCID: PMC10060507 DOI: 10.3389/fimmu.2023.1127572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/03/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND The disease burden caused by chronic hepatitis B virus (HBV) infection is still heavy, and the current treatment scheme has not achieved a complete cure. Changes in natural and adaptive immunity usually accompany chronic HBV infection. As a marker expressed on dendritic cells (DCs), whether lysosome-associated membrane glycoprotein 3 (LAMP3) participates in chronic HBV infection deserves further analysis. METHODS We retrieved chronic HBV infection transcriptional information from the Gene Expression Omnibus (GEO) database. The LAMP3 expression in the liver of patients with chronic hepatitis B (CHB) was analyzed in three GEO datasets and confirmed in our validation cohort (27 patients with CHB). Differentially expressed genes were obtained from one CHB cohort by comparing LAMP3high and LAMP3low expression subgroups. These genes underwent Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and Gene Set Enrichment Analysis to decipher the influence of LAMP3 on the biological process and immunity changes in HBV infection. Furthermore, we investigated the potential relationship between LAMP3 levels, the abundance of infiltrating immune cells, and liver dysfunction. RESULTS Compared to healthy controls, LAMP3 expression was upregulated in the transcriptional profiles of the liver in patients with CHB. The high LAMP3 expression was related to T cell activation and the chemokine signaling pathway. The LAMP3 gene was positively linked to marker sets of infiltrating activated regulatory T cells (Treg), T cell exhaustion, monocytes, and DCs. Moreover, CHB patients with high LAMP3 expression had unfavorable liver dysfunction. CONCLUSIONS LAMP3 is a gene related to HBV infection, which might be involved in HBV infection by regulating T cell activation and adaptive immune response.
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Affiliation(s)
- Zilong Wang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xiaoxiao Wang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Jin
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Feng Liu
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Huiying Rao
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Hongsong Chen
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Bo Feng
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
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13
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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14
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Chen C, Chuang W, Qin A, Zhang W, Zhu L, Zhang G, Chen J, Lo C, Zhou X, Mao X, Shang J, Kuo H, Xie W, Chen C, Lo G, Jun DW, Dang S, Tsai C, Wang T, Lai H, Tseng K, Huang Y, Chen P. A Phase 3 clinical trial validating the potency and safety of an innovative, extra-long-acting interferon in chronic hepatitis C. JGH Open 2022; 6:782-791. [PMID: 36406648 PMCID: PMC9667409 DOI: 10.1002/jgh3.12825] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/22/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND AIM Ropeginterferon alfa-2b is a novel mono-pegylated, extra-long-acting interferon. It is administered infrequently and showed good tolerability and clinical activity for the chronic hepatitis B or C treatment in our previous Phase 2 clinical trials. This study aims to validate the potency and safety of this novel agent in a Phase 3 chronic viral hepatitis setting. METHODS Patients with chronic hepatitis C genotype 2 were randomized to receive subcutaneous injections of ropeginterferon alfa-2b biweekly or the conventional pegylated interferon alfa-2b weekly for 24 weeks, combined with ribavirin. The primary endpoint was to assess the safety and antiviral potency of ropeginterferon alfa-2b by the non-inferiority in sustained virologic response at 12 weeks after treatment. RESULTS A total of 222 patients were enrolled. Ropeginterferon alfa-2b group showed a favorable safety profile. Side effects that were generally associated with prior interferon therapies, including neutropenia, asthenia, fatigue, alopecia, dizziness, decreased appetite, nausea, flu-like symptoms including myalgia, pyrexia, and headache, and administration site reactions, were notably less in the ropeginterferon alfa-2b group. The cumulative incidence of adverse events of special interest was also notably higher in the control group. The primary endpoint was met and ropeginterferon alfa-2b showed a better SVR12 rate of 79.8% than 71.9% of the control group. CONCLUSION Ropeginterferon alfa-2b is efficacious and has a favorable safety profile as compared with the conventional pegylated interferon alfa-2b. This study together with previous Phase 2 data validated ropeginterferon alfa-2b to be a new treatment option for chronic hepatitis C genotype 2.
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Affiliation(s)
- Chi‐Yi Chen
- Division of Gastroenterology and Hepatology, Department of MedicineDitmanson Medical Foundation Chiayi Christian HospitalChiayi CityTaiwan
| | - Wan‐Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis CenterKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung CityTaiwan
| | - Albert Qin
- PharmaEssentia CorporationTaipei CityTaiwan
| | - Wen‐Hua Zhang
- Department of Cancer Epidemiology, Wuwei Cancer RegistryGansu Wuwei Tumor HospitalWuweiChina
| | - Li‐Ying Zhu
- Department of Infectious DiseaseThe Fourth Hospital of Harbin Medical UniversityHarbinChina
| | - Guo‐Qiang Zhang
- Department of Infectious DiseaseLuoyang Central HospitalLuoyangChina
| | - Jyh‐Jou Chen
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTainan CityTaiwan
| | - Ching‐Chu Lo
- Department of Internal MedicineSt. Martin De Porres HospitalChiayi CityTaiwan
| | - Xinmin Zhou
- Department of GastroenterologyXijing Hospital, Air Force Medical UniversityXi'anChina
| | - Xiaorong Mao
- Departments of Infectious Diseases, The First Clinical Medical CollegeLanzhou UniversityLanzhouChina
| | - Jia Shang
- Department of Infectious DiseasesHenan Provincial People's HospitalZhengzhouChina
| | - Hsing‐Tao Kuo
- Division of Gastroenterology and Hepatology, Department of Internal MedicineChi‐Mei Medical Center – YongkangTainan CityTaiwan
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan HospitalCapital Medical UniversityBeijingChina
| | - Chien‐Hung Chen
- Division of Hepatogastroenterology, Department of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung CityTaiwan
| | - Gin‐Ho Lo
- Department of Medical Research, Digestive CenterE‐Da HospitalKaohsiung CityTaiwan
| | - Dae W Jun
- Department of Internal MedicineHanyang University, College of MedicineSeoulSouth Korea
| | - Shuangsuo Dang
- Department of Infectious DiseasesSecond Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | | | | | | | | | - Yi‐Wen Huang
- PharmaEssentia CorporationTaipei CityTaiwan
- Division of Gastroenterology and Hepatology, Department of Internal MedicineTaipei Medical University HospitalTaipei CityTaiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipei CityTaiwan
- School of MedicineNational Taiwan University College of MedicineTaipei CityTaiwan
| | - Pei‐Jer Chen
- Graduate Institute of Clinical MedicineNational Taiwan University College of MedicineTaipei CityTaiwan
- Hepatitis Research CenterNational Taiwan University HospitalTaipei CityTaiwan
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15
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Shetty VV, Kellarai A. Comprehensive Review of Hepatocellular Carcinoma in India: Current Challenges and Future Directions. JCO Glob Oncol 2022; 8:e2200118. [PMID: 36198133 PMCID: PMC9812497 DOI: 10.1200/go.22.00118] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
There is not much information on hepatocellular carcinoma (HCC) in India. Here, we review the existing data, available treatment choices, and future directions in HCC management. An extensive search was conducted through PubMed and MEDLINE for studies published between January 2000 and June 2022 on the epidemiology of HCC in India using the following key words: atezolizumab, BCLC staging, hepatocellular carcinoma, immune checkpoint inhibitors, immunotherapy, and programmed cell death ligand-1, with the filters humans and English language. The most frequent risk factors for the development of HCC in India include nonalcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infection, liver cirrhosis, and alcohol intake. On the basis of new findings, the Barcelona Clinic Liver Cancer (BCLC) Staging Criteria need to be revised. As most cases in India are discovered at a later stage, curative treatments such as surgical resection, ablation, or liver transplantation may not be an option. Clinical trials are underway for a number of immune checkpoint drugs that target cytotoxic T-cell lymphocyte-4 and programmed cell death-1/programmed cell death-ligand 1. In India, phase III trials of atezolizumab in combination with other drugs are underway for the treatment of various malignancies. Renin angiotensin system inhibitors, antivirals, primary hepatocyte transplantation, and bioartificial liver devices are among the future options for the management of HCC. In developing countries like India, HCC is often diagnosed at an advanced stage because of a delay in routine testing or screening. Therefore, developing effective treatment regimens for such stages is critical. Immunotherapy is a promising treatment option that has the potential to increase overall response and survival rate.
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Affiliation(s)
- Vijith Vittal Shetty
- K.S Hegde Medical Academy, Mangalore, India,Vijith Vittal Shetty, MD, DM, Medical Oncology, K.S Hegde Medical Academy, University Rd, Deralakatte, Mangalore, Dakshina Kannada, Karnataka 575018, India; e-mail:
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16
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Zhu Y, Qin LX. Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:420-429. [PMID: 35977874 DOI: 10.1016/j.hbpd.2022.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023]
Abstract
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
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Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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17
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Liu Y, Liu L. Changes in the Epidemiology of Hepatocellular Carcinoma in Asia. Cancers (Basel) 2022; 14:cancers14184473. [PMID: 36139633 PMCID: PMC9496757 DOI: 10.3390/cancers14184473] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary The incidence and mortality of hepatocellular carcinoma (HCC) in Asia are among the world leaders. By understanding the changes in prevalence and influencing factors of HCC, we can better understand the current situation in Asia and take measures to reduce the incidence. Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with high morbidity and mortality, and the incidence is on the rise. HCC imposes a heavy healthcare burden on Asian countries due to the presence of multiple HCC risk factors in this area. Chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, non-alcoholic liver disease (NAFLD), aflatoxin and alcohol intake are the causes of HCC that cannot be ignored. Compared with the pre-vaccination era, universal vaccination of newborns reduces the incidence of HCC. Anti-viral therapy with nucleos(t)ide analogues also causes a decline in HCC incidence. Early screening and direct-acting antiviral agent are beneficial to the prevention and treatment of HCV. For HCC caused by NAFLD and other reasons, lifestyle changes are imperative. This paper introduces the epidemiological trends of HCC in Asia and highlight future efforts. Focusing on prevention may be the most effective way to improve the prognosis of this hard-to-treat cancer.
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Affiliation(s)
- Yao Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei 230001, China
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei 230001, China
- Correspondence:
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18
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Wang X, Gao X, Wu R, Chi X, Xu H, Guan Y, Jin Q, Niu J. Serum qAnti-HBc combined with ALT and HBsAg predicts significant hepatic inflammation in HBeAg-positive immune active patients. J Gastroenterol Hepatol 2022; 37:1806-1814. [PMID: 35509262 DOI: 10.1111/jgh.15881] [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: 12/21/2021] [Revised: 04/14/2022] [Accepted: 05/01/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Quantitative hepatitis B core antibody (qAnti-HBc) level has been reported to predict significant liver inflammation in treatment-naïve chronic hepatitis B patients. However, little evidence has been revealed that qAnti-HBc alone or with other serum parameters in predicting moderate to severe hepatic inflammation in HBeAg-positive immune active patients treated with entecavir (ETV). METHODS A total of 142 patients with HBeAg-positive immune active hepatitis were recruited in our study. Serum liver biochemistry, qAnti-HBc, hepatitis B virus markers, and liver inflammation were evaluated during 48-week ETV treatment. The association between liver inflammation grades and serum markers was systematically analyzed. RESULTS The patients with moderate to severe inflammation (≥ G2) had a significantly higher level of qAnti-HBc compared with those with no to mild liver inflammation patients (< G2). The levels of qAnti-HBc and alanine transaminase (ALT) were positively correlated with hepatic inflammation grades, and qAnti-HBc had a better correlation than ALT, whereas HBsAg was negatively correlated with hepatic inflammation grades before treatment. After 48-week ETV treatment, no correlation was observed between hepatic inflammation grades and qAnti-HBc, ALT, or HBsAg. The combination of qAnti-HBc, ALT, and HBsAg had better performance in predicting significant liver inflammation (≥ G2) than qAnti-HBc alone or its combination with ALT. CONCLUSION Serum qAnti-HBc levels were positively correlated with hepatic inflammation grades before treatment, but no positive correlation between them was observed after 48-week treatment. The level of qAnti-HBc combined with ALT and HBsAg may serve as a more reliable marker for identifying significant liver inflammation before treatment in HBeAg-positive immune active patients.
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Affiliation(s)
- Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiuzhu Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Ruihong Wu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiumei Chi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Yazhe Guan
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Qinglong Jin
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China.,Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, China
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Abstract
The last few years have seen a resurgence of activity in the hepatitis B drug pipeline, with many compounds in various stages of development. This review aims to provide a comprehensive overview of the latest advances in therapeutics for chronic hepatitis B (CHB). We will discuss the broad spectrum of direct-acting antivirals in clinical development, including capsids inhibitors, siRNA, HBsAg and polymerase inhibitors. In addition, host-targeted therapies (HTT) will be extensively reviewed, focusing on the latest progress in immunotherapeutics such as toll-like receptors and RIG-1 agonists, therapeutic vaccines and immune checkpoints modulators. A growing number of HTT in pre-clinical development directly target the key to HBV persistence, namely the covalently closed circular DNA (cccDNA) and hold great promise for HBV cure. This exciting area of HBV research will be highlighted, and molecules such as cyclophilins inhibitors, APOBEC3 deaminases and epigenetic modifiers will be discussed.
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Affiliation(s)
- Sandra Phillips
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
| | - Ravi Jagatia
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
| | - Shilpa Chokshi
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
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20
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Burdette DL, Lazerwith S, Yang J, Chan HLY, Delaney IV WE, Fletcher SP, Cihlar T, Feierbach B. Ongoing viral replication and production of infectious virus in patients with chronic hepatitis B virus suppressed below the limit of quantitation on long-term nucleos(t)ide therapy. PLoS One 2022; 17:e0262516. [PMID: 35363817 PMCID: PMC8974970 DOI: 10.1371/journal.pone.0262516] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/28/2021] [Indexed: 01/05/2023] Open
Abstract
Nucleos(t)ide analogs are standard-of-care for the treatment of chronic hepatitis B and can effectively reduce hepatitis B virus (HBV) replication but rarely leads to cure. Nucleos(t)ide analogs do not directly eliminate the viral episome, therefore treatment cessation typically leads to rapid viral rebound. While treatment is effective, HBV DNA is still detectable (although not quantifiable) in the periphery of the majority of nucleos(t)ide analog treated HBV patients, even after prolonged treatment. Addressing whether the detectable HBV DNA represents infectious virus is a key unknown and has important implications for the development of a curative treatment for HBV. The minimum HBV genome equivalents required to establish infection in human liver chimeric mice was determined by titration of HBV patient sera and the infectivity in chimeric mice of serum from patients (n = 7) suppressed to the limit of detection on nucleos(t)ide analog therapy was evaluated. A minimum of 5 HBV genome equivalents were required to establish infection in the chimeric mice, confirming this model has sufficient sensitivity to determine whether serum from virally suppressed patients contains infectious virus. Strikingly, serum from 75% (n = 3 out of 4) of nucleos(t)ide-treated HBV patients with DNA that was detectable, but below the lower limit of quantitation, also established infection in the chimeric mice. These results demonstrate that infectious virus is still present in some HBV patients on suppressive nucleos(t)ide therapy. This residual virus may support viral persistence via continuous infection and explain the ongoing risk for HBV-related complications despite long-term suppression on therapy. Thus, additional treatment intensification may facilitate HBV cure.
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Affiliation(s)
- Dara L Burdette
- Discovery Virology, Gilead Sciences, Foster City, CA, United States of America
| | - Scott Lazerwith
- Medicinal Chemistry, Gilead Sciences, Foster City, CA, United States of America
| | - Jenny Yang
- Clinical Research, Gilead Sciences, Foster City, CA, United States of America
| | | | | | - Simon P. Fletcher
- Discovery Virology, Gilead Sciences, Foster City, CA, United States of America
| | - Tomas Cihlar
- Discovery Virology, Gilead Sciences, Foster City, CA, United States of America
| | - Becket Feierbach
- Clinical Virology, Gilead Sciences, Foster City, CA, United States of America
- * E-mail:
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21
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Hirode G, Choi HSJ, Chen CH, Su TH, Seto WK, Van Hees S, Papatheodoridi M, Lens S, Wong G, Brakenhoff SM, Chien RN, Feld J, Sonneveld MJ, Chan HLY, Forns X, Papatheodoridis GV, Vanwolleghem T, Yuen MF, Hsu YC, Kao JH, Cornberg M, Hansen BE, Jeng WJ, Janssen HLA. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study). Gastroenterology 2022; 162:757-771.e4. [PMID: 34762906 DOI: 10.1053/j.gastro.2021.11.002] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). METHODS This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. RESULTS Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. CONCLUSIONS The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.
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Affiliation(s)
- Grishma Hirode
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada
| | | | - Tung-Hung Su
- National Taiwan University Hospital, Taipei, Taiwan
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Stijn Van Hees
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | | | - Sabela Lens
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Grace Wong
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Sylvia M Brakenhoff
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Jordan Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Henry L Y Chan
- The Chinese University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Xavier Forns
- Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | | | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Special administrative regions of China
| | - Yao-Chun Hsu
- E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | | | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany Centre for Individualized Infection Medicine, Hannover, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; The Toronto Viral Hepatitis Care Network, Toronto, Canada.
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22
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Liu Z, Zhang Y, Xu M, Li X, Zhang Z. Distribution of hepatitis B virus genotypes and subgenotypes: A meta-analysis. Medicine (Baltimore) 2021; 100:e27941. [PMID: 34918643 PMCID: PMC8678021 DOI: 10.1097/md.0000000000027941] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/19/2020] [Accepted: 11/04/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) genotypes and subgenotypes have distinct geographical distributions and influence a number of clinical disease features and responses to treatment. There are many reports on the distribution of HBV genotypes, but great differences are present between studies. What's more, a meta-analysis of HBV genotype- and subgenotype-distribution by country is lacking.A comprehensive literature search was performed in PubMed and a systematic search of full-length HBV sequences and S gene sequences was conducted in the GenBank database. HBV genotypes were checked and subgenotypes were determined by phylogenetic comparison of full-length HBV sequences or S gene sequences. STATA 12.0 was used for the analysis for countries with multiple datasets. BEAST 2.5.2 was used for Bayesian phylogenetic analysis to infer the evolutionary time scales of HBV.This study includes 309 datasets from 110 countries, including 188 relevant studies, 58 full-length gene datasets, and 63 S gene datasets. The meta-analysis was performed on 274 datasets from 75 countries. The distribution of genotypes is more detailed than those described by previous studies. While the overall genotype distribution is similar to that reported in previous studies, some notable aspects were different. The main genotypes present in south-eastern Africa, North Africa, and West Africa are genotypes A, D, and E, respectively. Genotypes G and H are mainly distributed in Mexico. Genotype F is mainly distributed in central and South America, but genotypes A and D are also common in Brazil, Cuba, and Haiti.This study provides a more accurate description of the distribution of HBV genotypes and subgenotypes in different countries and suggests that the differences in genotype distribution may be related to ethnicity and human migration.
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23
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Chang Y, Kim SG, Jeong SW, Jang JY, Yoo JJ, Lee SH, Kim YS, Kim HS, Lee HW, Park S. Efficacy and Safety of Tenofovir Disoproxil Orotate in Chronic Hepatitis B Patients Previously Treated with Tenofovir Disoproxil Fumarate: Multicenter, Open-Label, Prospective Study. J Clin Med 2021; 10:jcm10235628. [PMID: 34884330 PMCID: PMC8658686 DOI: 10.3390/jcm10235628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/20/2021] [Accepted: 11/25/2021] [Indexed: 11/16/2022] Open
Abstract
Background/Aim: We aimed to demonstrate the efficacy and safety of tenofovir disoproxilorotate (TDO) compared with that of tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B. Methods: This multicenter, open-label, prospective clinical trial (KCT0004185) was conducted to evaluate the efficacy and safety of TDO on switching from TDF for 24 weeks in virologically suppressed chronic hepatitis B patients. The primary efficacy endpoint was the maintenance of virologic response. Safety was assessed by evaluating major adverse events, changes in renal function, and occurrence of hepatocellular carcinoma (HCC). Results: TDO treatment was not inferior in terms of virological response when compared with that on TDF treatment, with a noninferiority margin of −10% (risk difference, −3.17%; 95% confidence interval, −7.5–1.15%). The biological response of TDO was also comparable to that of TDF, with no significant difference in the proportion of patients with normalized alanine transaminase levels. After 24 weeks of treatment, hepatitis B core-related antigen (HBcrAg) significantly decreased to a mean titer of 3.91 log U/mL from 4.15 log U/mL at baseline (p = 0.01). There were no cases of grade 3 or higher adverse events and HCC. The mean estimated glomerular filtration rate increased from 91.09 mL/min to 93.34 mL/min (p = 0.056), and the mean serum level of phosphorus increased from 3.33 mg/dL to 3.44 mg/dL (p = 0.045), suggesting improvement in renal function with TDO treatment. Conclusion: In patients with chronic hepatitis B, the efficacy of TDO was noninferior to that of TDF, with a significant decrease in the HBcrAg titer and improved renal function.
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Affiliation(s)
- Young Chang
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
| | - Sang-Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Soung-Won Jeong
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
- Correspondence: (S.-W.J.); (H.-W.L.)
| | - Jae-Young Jang
- Digestive Disease Center, Department of Internal Medicine, Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (J.-Y.J.)
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Sae-Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.-H.L.); (H.-S.K.)
| | - Young-Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (S.-G.K.); (J.-J.Y.); (Y.-S.K.)
| | - Hong-Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.-H.L.); (H.-S.K.)
| | - Hyun-Woong Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea
- Correspondence: (S.-W.J.); (H.-W.L.)
| | - Suyeon Park
- Department of Biostatistics, Soonchunhyang University Hospital, Seoul 04401, Korea;
- Department of Applied Statistics, Chung-Ang University, Seoul 06974, Korea
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24
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Liu J, Wang J, Yan X, Xue R, Zhan J, Jiang S, Geng Y, Liu Y, Mao M, Xia J, Yin S, Tong X, Chen Y, Ding W, Huang R, Wu C. Presence of Liver Inflammation in Asian Patients With Chronic Hepatitis B With Normal ALT and Detectable HBV DNA in Absence of Liver Fibrosis. Hepatol Commun 2021; 6:855-866. [PMID: 34783181 PMCID: PMC8948668 DOI: 10.1002/hep4.1859] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/16/2021] [Accepted: 10/26/2021] [Indexed: 02/06/2023] Open
Abstract
Liver biopsies are recommended to exclude significant liver inflammation in patients with chronic hepatitis B (CHB) with elevated HBV DNA but without other indications for antiviral treatment. We aimed to investigate the proportions and determinants of significant inflammation in Asian patients with CHB with detectable HBV DNA. We conducted a cross‐sectional study that retrospectively included 581 patients with CHB with detectable HBV DNA who had undergone liver biopsy. Liver inflammation and fibrosis were staged by Scheuer’s classification. Significant inflammation and significant fibrosis were defined as G ≥ 2 and S ≥ 2, respectively. There were 179 (30.8%) patients with alanine aminotransferase (ALT) < 1 × upper limit of normal (ULN), 205 (35.3%) patients with ALT 1‐2 × ULN, and 197 (33.9%) patients with ALT > 2 × ULN. A total of 397 (68.3%) patients had significant inflammation, and 340 (58.5%) patients had significant fibrosis. Significant inflammation was found in 85% of patients with significant fibrosis and in 44.8% of patients without significant fibrosis. Furthermore, 28.7% of patients with CHB with detectable HBV DNA and normal ALT in the absence of significant fibrosis had significant inflammation. Moderate HBV DNA (5‐7 log10 IU/mL) was a risk factor for significant inflammation (odds ratio [OR] 6.929, 95% confidence interval [CI] 2.830‐16.966, P < 0.001) in patients with CHB with detectable HBV DNA, especially for patients with detectable HBV DNA and normal ALT in the absence of significant fibrosis (adjusted OR 13.161, 95% CI 1.026‐168.889, P = 0.048). Conclusion: A high proportion of CHB patients with detectable HBV DNA and normal ALT in the absence of significant fibrosis have significant liver inflammation. Liver biopsies are recommended to evaluate liver inflammation in such patients, especially for those with moderate HBV DNA.
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Affiliation(s)
- Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Ruifei Xue
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Zhan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Suling Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Geng
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Minxin Mao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China.,Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
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25
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Abstract
Hepatitis B virus (HBV) is the one of most common causes of the hepatocellular carcinoma (HCC), especially in eastern world. The aim of this review is to try to understand the relationship between HBV and HCC and to reveal the role of prevention and treatment of HBV infection in reducing the incidence of HCC. Strategies to prevent HCC due to HBV can be classified into three categories. These are primary, secondary, and tertiary preventions. Hepatitis B vaccine is now in the most vital position in preventing HBV-associated HCC. In patients with chronic hepatitis B infection, suppressing viral load with potent antivirals such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV) prevents the development of HCC and improves prognosis by reducing recurrence after HCC treatments. There is currently no clear consensus on which of these drugs should be preferred. Although data on tenofovir alafenamide (TAF) are scarce, available data with TDF suggest that TAF therapy will also be a strong actor for HCC.
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26
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Liang KH, Chen SF, Lin YH, Chu YD, Lin YH, Lai MW, Lin CL, Yeh CT. Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9111539. [PMID: 34829768 PMCID: PMC8614833 DOI: 10.3390/biomedicines9111539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/17/2021] [Accepted: 10/22/2021] [Indexed: 01/04/2023] Open
Abstract
Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The N-Acetylgalactosaminyltransferase 14 (GALNT14) gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], p = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; p = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib.
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Affiliation(s)
- Kung-Hao Liang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: (K.-H.L.); (C.-T.Y.); Tel.: +886-2-28712121 (ext. 1296) (K.-H.L.); +886-3-3281200 (ext. 8129) (C.-T.Y.); Fax: 886-3-3282824 (C.-T.Y.)
| | - Sung-Fang Chen
- Department of Chemistry, National Taiwan Normal University, Taipei 106, Taiwan; (S.-F.C.); (Y.-H.L.)
| | - Yu-Hua Lin
- Department of Chemistry, National Taiwan Normal University, Taipei 106, Taiwan; (S.-F.C.); (Y.-H.L.)
| | - Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
- Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
- Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung 204, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan; (Y.-D.C.); (Y.-H.L.); (M.-W.L.); (C.-L.L.)
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (K.-H.L.); (C.-T.Y.); Tel.: +886-2-28712121 (ext. 1296) (K.-H.L.); +886-3-3281200 (ext. 8129) (C.-T.Y.); Fax: 886-3-3282824 (C.-T.Y.)
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27
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Sandmann L, Cornberg M. Towards eradication of HBV: Treatment approaches and status of clinical trials. Curr Opin Pharmacol 2021; 60:232-240. [PMID: 34474210 DOI: 10.1016/j.coph.2021.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/08/2021] [Accepted: 07/07/2021] [Indexed: 01/05/2023]
Abstract
Chronic hepatitis B virus (HBV) infection and its sequelae remain a global health challenge. Current treatments are effective in controlling HBV replication, but complete eradication or 'cure' of HBV remains a rare event and is difficult to assess because of the intrahepatic reservoir of covalently closed circular DNA. Based on the understanding of the HBV life cycle and the deciphering of immune responses to HBV, therapeutic strategies to target HBV eradication are in principle possible. This article reviews current developments in new therapies aimed at HBV cure.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School Hannover, Germany; Centre for Individualised Infection Medicine (CiiM), a Joint Venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany.
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28
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Sterling RK, King WC, Khalili M, Chung RT, Sulkowski M, Jain MK, Lisker-Melman M, Ghany MG, Wong DK, Hinerman AS, Bhan AK, Wahed AS, Kleiner DE. A Prospective Study Evaluating Changes in Histology, Clinical and Virologic Outcomes in HBV-HIV Co-infected Adults in North America. Hepatology 2021; 74:1174-1189. [PMID: 33743541 PMCID: PMC8597319 DOI: 10.1002/hep.31823] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/11/2021] [Accepted: 03/05/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined. APPROACH AND RESULTS Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm3 and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P = 0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P = 0.58). CONCLUSIONS In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.
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Affiliation(s)
| | - Wendy C King
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
| | | | - Raymond T Chung
- Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | | | | | | | | | - Amanda S Hinerman
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
| | - Atul K Bhan
- Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Abdus S Wahed
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
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29
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Ricciotti E, Wangensteen KJ, FitzGerald GA. Aspirin in Hepatocellular Carcinoma. Cancer Res 2021; 81:3751-3761. [PMID: 33893087 DOI: 10.1158/0008-5472.can-21-0758] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 01/27/2023]
Abstract
Preclinical and clinical studies provide evidence for aspirin as a preventative agent for cancer. Compelling direct evidence supports a chemopreventive effect of aspirin in individuals at high risk of developing colorectal cancer due to Lynch syndrome, while indirect evidence indicates that aspirin may reduce the risk of and mortality from sporadic colorectal cancer. There is weaker evidence for a protective effect of aspirin against all cancers taken as a group. Nevertheless, the results of recent retrospective cohort studies consistently indicate a beneficial effect of aspirin as a chemopreventive or adjuvant chemotherapeutic agent in hepatocellular carcinoma (HCC). Epidemiologic studies conducted in the general population or in selected populations at higher risk for HCC reveal that regular aspirin use is associated with reduced HCC incidence. In addition, aspirin may act as an adjuvant to other therapies in reducing HCC recurrence. According to studies in animal models, the cancer-preventative effect of aspirin may be related to its antiplatelet and anti-inflammatory activities. Prospective studies are warranted to determine whether aspirin should be recommended to diverse populations of patients at risk for HCC.
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Affiliation(s)
- Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kirk J Wangensteen
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Garret A FitzGerald
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. .,Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Wang X, Liu X, Dang Z, Yu L, Jiang Y, Wang X, Yan Z. Nucleos(t)ide Analogues for Reducing Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. Gut Liver 2021. [PMID: 31158948 DOI: 10.5009/gnl18546.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Studies have shown that nucleos(t)ide analogue (NA) treatment can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it is unclear which NA is most effective. We performed a meta-analysis and systematic review comparing the efficacies of NAs in CHB patients. Methods We searched literature databases for randomized controlled trials (RCTs) and observational studies that analyzed the hepatic biochemical response, virological response, seroconversion rate, drug resistance rate, and HCC incidence rate in CHB patients treated with NAs. Meta-analyses were performed with RevMan and Stata/SE software. Results Twelve cohort studies and one RCT were selected, in which entecavir (ETV), lamivudine (LAM), telbivudine (LdT), and/or tenofovir disoproxil fumarate (TDF) were evaluated in CHB patients. The meta-analysis showed that ETV was superior to LAM with regard to the HCC incidence (p<0.001), biochemical response (p=0.001), virological response (p=0.02), and drug resistance (p<0.001), and ETV was superior to LdT with regard to the virological response (p<0.001) and drug resistance (p<0.001). We found no significant difference between ETV and TDF with regard to the HCC incidence (p=0.08), biochemical response (p=0.39), virological response (p=0.31), serological conversion (p=0.38), or drug resistance (p=0.95). NA-treated patients with pre-existing cirrhosis had a 5.49 times greater incidence of HCC than those without cirrhosis (p<0.001). Conclusions ETV or TDF should be used for long-term first-line monotherapy in CHB patients according to the current guidelines. Standardized protocols are needed for future studies of ETV and TDF to facilitate conclusive comparisons. Patients with cirrhosis are at significantly elevated risk for HCC, despite the benefits of NA treatment.
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Affiliation(s)
- Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhibo Dang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiyun Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Wang X, Liu X, Dang Z, Yu L, Jiang Y, Wang X, Yan Z. Nucleos(t)ide Analogues for Reducing Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. Gut Liver 2021; 14:232-247. [PMID: 31158948 PMCID: PMC7096226 DOI: 10.5009/gnl18546] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/12/2019] [Accepted: 04/05/2019] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Studies have shown that nucleos(t)ide analogue (NA) treatment can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it is unclear which NA is most effective. We performed a meta-analysis and systematic review comparing the efficacies of NAs in CHB patients. Methods We searched literature databases for randomized controlled trials (RCTs) and observational studies that analyzed the hepatic biochemical response, virological response, seroconversion rate, drug resistance rate, and HCC incidence rate in CHB patients treated with NAs. Meta-analyses were performed with RevMan and Stata/SE software. Results Twelve cohort studies and one RCT were selected, in which entecavir (ETV), lamivudine (LAM), telbivudine (LdT), and/or tenofovir disoproxil fumarate (TDF) were evaluated in CHB patients. The meta-analysis showed that ETV was superior to LAM with regard to the HCC incidence (p<0.001), biochemical response (p=0.001), virological response (p=0.02), and drug resistance (p<0.001), and ETV was superior to LdT with regard to the virological response (p<0.001) and drug resistance (p<0.001). We found no significant difference between ETV and TDF with regard to the HCC incidence (p=0.08), biochemical response (p=0.39), virological response (p=0.31), serological conversion (p=0.38), or drug resistance (p=0.95). NA-treated patients with pre-existing cirrhosis had a 5.49 times greater incidence of HCC than those without cirrhosis (p<0.001). Conclusions ETV or TDF should be used for long-term first-line monotherapy in CHB patients according to the current guidelines. Standardized protocols are needed for future studies of ETV and TDF to facilitate conclusive comparisons. Patients with cirrhosis are at significantly elevated risk for HCC, despite the benefits of NA treatment.
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Affiliation(s)
- Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhibo Dang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiyun Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Farag MS, van Campenhout MJH, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, van Vuuren AJ, Ferenci P, Feld JJ, Berg T, Hansen BE, van Bömmel F, Janssen HLA. Hepatitis B Virus RNA as Early Predictor for Response to Pegylated Interferon Alpha in HBeAg-Negative Chronic Hepatitis B. Clin Infect Dis 2021; 72:202-211. [PMID: 31912157 DOI: 10.1093/cid/ciaa013] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/06/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatitis B virus RNA (HBV-RNA) is a novel serum biomarker that correlates with transcription of intrahepatic covalently closed circular (cccDNA), which is an important target for pegylated interferon (PEG-IFN) and novel therapies for functional cure. We studied HBV-RNA kinetics following PEG-IFN treatment and its potential role as a predictor to response in HBeAg-negative chronic hepatitis B (CHB) patients. METHODS HBV-RNA levels were measured in 133 HBeAg-negative CHB patients treated in an international randomized controlled trial (PARC study). Patients received PEG-IFN α-2a for 48 weeks. HBV-RNA was measured from baseline through week 144. Response was defined as HBV-DNA <2000 IU/mL and ALT normalization at week 72. Kinetics of HBV-RNA were compared with HBV-DNA, HBsAg, and HBcrAg. RESULTS Mean HBV-RNA at baseline was 4.4 (standard deviation [SD] 1.2) log10 c/mL. At week 12, HBV-RNA declined by -1.6 (1.1) log10 c/mL. HBV-RNA showed a greater decline in responders compared to nonresponders early at week 12 (-2.0 [1.2] vs -1.5 [1.1] log10 c/mL, P = .04). HBV-RNA level above 1700 c/mL (3.2 log10 c/mL) had a negative predictive value of 91% at week 12 and 93% at week 24 (P = .01) for response. Overall, HBV-RNA showed a stronger correlation with HBV-DNA and HBcrAg (.82 and .80, P < .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (<100 IU/mL) or HBsAg loss at week 144. CONCLUSIONS During PEG-IFN treatment for HBeAg-negative CHB, HBV-RNA showed a fast and significant decline that correlates with treatment response and HBsAg loss at long-term follow-up. CLINICAL TRIALS REGISTRATION NCT00114361.
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Affiliation(s)
- Mina S Farag
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Maria Pfefferkorn
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Janett Fischer
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Danilo Deichsel
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Anneke J van Vuuren
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Peter Ferenci
- Department of Internal Medicine 3, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Thomas Berg
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Florian van Bömmel
- University Hospital Leipzig, Department of Gastroenterology and Rheumatology, Section of Hepatology, Leipzig, Germany
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
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Abstract
Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population starting from birth dose, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective, the cancer preventive efficacy support it as the first successful example of cancer preventive vaccine in human. Addition of hepatitis B immunoglobulin immediately after birth and antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are existing or possible emerging strategies to enhance the prevention efficacy of HBV infection and its related liver cancer. Secondary prevention with current antiviral agents may reduce the risk or delay the onset of HCC development, but could not eradicate HBV infection and HCC. Better antiviral therapeutic agents are needed for better secondary prevention.
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Affiliation(s)
- Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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Abstract
Chronic hepatitis B virus (HBV) infection impacts an estimated 257-291 million people globally. The current approach to treatment for chronic HBV infection is complex, reflecting a risk:benefit approach driven by the lack of an effective curative regimen. This complexity and the lack of a durable treatment response, necessitating indefinite treatment in the majority of cases, have resulted in low uptake of testing and treatment, particularly in regions where comprehensive primary care is lacking and access to affordable testing and treatment is limited. Multiple targeted therapies are now in early human study with the primary goal to achieve persistent HBV DNA and hepatitis B surface antigen suppression after a finite course of treatment, which is referred to as functional cure. This article summarizes the current therapies for HBV infection and discusses the limitations of these therapies, novel approaches to HBV cure, and therapeutic endpoints of clinical trials aimed to cure hepatitis B.
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Affiliation(s)
- Susanna Naggie
- Department of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina 27701, USA; .,Duke Clinical Research Institute, Durham, North Carolina 27701, USA
| | - Anna S Lok
- Department of Internal Medicine-Gastroenterology and Hepatology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA;
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Wang X, Wang Z, Chi X, Wu R, Jin Q, Xu H, Gao X, Yu L, Chen Y, Shang J, Liu L, Zhang S, Jiang Y, Zhang M, Tong Q, Zhang L, Tan Y, Ma A, Dang S, Xu B, Jin Z, Li J, Li X, Lu F, Niu J. Efficacy of a combination of HBV RNA and HBeAg in predicting HBeAg seroconversion in patients treated with entecavir for 144 weeks. Int J Infect Dis 2020; 99:171-178. [PMID: 32721532 DOI: 10.1016/j.ijid.2020.07.031] [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: 05/20/2020] [Revised: 07/08/2020] [Accepted: 07/18/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND In some previous studies, serum hepatitis B virus RNA (HBV RNA) was proposed as an HBV viral marker during therapy. However, the dynamic change of HBV RNA, the correlation of HBV RNA with cccDNA, and the combination of HBV RNA with known HBV markers in predicting entecavir (ETV) treatment outcome in the same cohort are rarely reported. METHODS A total of 111 HBeAg-positive patients were enrolled in our study. The dynamic changes of serum HBV RNA and the correlation of HBV RNA with other HBV markers were investigated in the early treatment period of 144-week ETV treatment. Intrahepatic cccDNA was detected at baseline and week 48. Receiver operating characteristic analyses were used to identify HBV RNA levels associated with HBeAg seroconversion. RESULTS The serum HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. The levels of HBV RNA decreased slower compared with the serum HBV DNA, irrespective of whether the patients achieved HBeAg seroconversion or not. Although the serum HBV RNA was positively correlated with cccDNA at baseline among all patients, no significant correlation was observed in the patients with HBeAg seroconversion at week 48 (r=0.094, P=0.588). The area under the receiver operating characteristic (AUROC) of HBV RNA and HBeAg at week 24 was 0.754 and 0.800, respectively. The AUROC of the HBV RNA and HBeAg combination had a higher value (AUROC=0.821). CONCLUSIONS The level of HBV RNA at week 24 was a powerful predictor of HBeAg seroconversion in HBeAg-positive patients after 144-week ETV treatment, while the combination of HBV RNA and HBeAg was superior to HBV RNA alone in predicting HBeAg seroconversion.
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Affiliation(s)
- Xiaomei Wang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Zhongfeng Wang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Xiumei Chi
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Ruihong Wu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Qinglong Jin
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Hongqin Xu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Xiuzhu Gao
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Lei Yu
- Department of Hepatology, Fourth Hospital of Harbin Medical University, Harbin, China
| | - Yuping Chen
- Department of Hepatology, Baoding Infectious Disease Hospital, Baoding, China
| | - Jia Shang
- Department of Hepatology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Longgen Liu
- Department of Hepatology, Changzhou Third People's Hospital, Changzhou, China
| | - Shuqin Zhang
- Department of Hepatology, Hepatology Hospital of Jilin Province, Changchun, China
| | - Yongfang Jiang
- Department of Hepatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Mingxiang Zhang
- Department of Infectious Disease, Shenyang Sixth People's Hospital, Shenyang, China
| | - Qiaoxia Tong
- Department of Infectious Disease, Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Lunli Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Youwen Tan
- Department of Hepatology, The Third People's Hospital of Zhenjiang, Zhenjiang, China
| | - Anlin Ma
- Department of Infectious Disease, China-Japan Friendship Hospital, Beijing, China
| | - Shuangsuo Dang
- Department of Infectious Disease, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Bin Xu
- Department of Hepatology, Beijing You'an Hoapital, Capital Medical University, Beijing, China
| | - Zhenjing Jin
- Department of Hepatology, the Second Hospital of Jilin University, Changchun, China
| | - Jia Li
- Department of Hepatology, the Second Hospital of Tianjin, Tianjing, China
| | - Xiaobo Li
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Fengmin Lu
- Department of Microbiology, Peking University Health Science Center, Beijing, China.
| | - Junqi Niu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China.
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Lau KC, Burak KW, Coffin CS. Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis. Microorganisms 2020; 8:E1470. [PMID: 32987867 PMCID: PMC7599633 DOI: 10.3390/microorganisms8101470] [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: 08/26/2020] [Revised: 09/16/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.
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Affiliation(s)
- Keith C.K. Lau
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
| | - Kelly W. Burak
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
| | - Carla S. Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
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Liang LY, Wong VWS, Toyoda H, Tse YK, Yip TCF, Yuen BWY, Tada T, Kumada T, Lee HW, Lui GCY, Chan HLY, Wong GLH. Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients. J Gastroenterol 2020; 55:899-908. [PMID: 32556643 DOI: 10.1007/s00535-020-01700-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/08/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis B core-related antigen (HBcrAg) is a novel serum viral marker. Recent studies showed that its level correlates with the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to evaluate the accuracy of serum HBsAg and HBcrAg levels at baseline to predict HCC. METHODS 1400 CHB patients who received nucleos(t)ide analogues (NA) treatment since December 2005 were included. Their stored serum samples at baseline were retrieved to measure HBsAg and HBcrAg levels. The primary endpoint was the cumulative incidence of HCC. RESULTS 85 (6.1%) patients developed HCC during a mean (± SD) follow-up duration of 45 ± 20 months. Serum HBcrAg level above 2.9 log10 U/mL at baseline was an independent factor for HCC in hepatitis B e antigen (HBeAg)-negative patients by multivariable analysis (adjusted hazard ratio 2.13, 95% CI 1.10-4.14, P = 0.025). HBcrAg above 2.9 log10 U/mL stratified the risk of HCC in HBeAg-negative patients with high PAGE-B score (P = 0.024 by Kaplan-Meier analysis), and possibly in cirrhotic patients (P = 0.08). Serum HBsAg level did not show any correlation with the risk of HCC in all patients or any subgroups. CONCLUSION Serum HBcrAg level predicts the risk of HCC accurately in NA-treated HBeAg-negative CHB patients.
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Affiliation(s)
- Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | | | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Becky Wing-Yan Yuen
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | | | | | - Hye-Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong.
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
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Hall S, Howell J, Visvanathan K, Thompson A. The Yin and the Yang of Treatment for Chronic Hepatitis B-When to Start, When to Stop Nucleos(t)ide Analogue Therapy. Viruses 2020; 12:v12090934. [PMID: 32854335 PMCID: PMC7552074 DOI: 10.3390/v12090934] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed "treat-all" strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of "stopping" NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the "treat-all" strategy, as well as the "stop" strategy, and how they may both have a role in the management of patients with chronic hepatitis B.
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Affiliation(s)
- Samuel Hall
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
- Correspondence:
| | - Jessica Howell
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
| | - Kumar Visvanathan
- Infectious Diseases Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia;
| | - Alexander Thompson
- Gastroenterology Department, St Vincent’s Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia; (J.H.); (A.T.)
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Wei Y, Yi Y, Tao C, Ye W, Zhao W. Impact of antiviral therapy with nucleos(t)ide analog on survival of patients with HBV-related small hepatocellular carcinomas. Cancer Manag Res 2019; 11:8475-8486. [PMID: 31572002 PMCID: PMC6756155 DOI: 10.2147/cmar.s201744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 08/05/2019] [Indexed: 01/27/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading causes of cancer-related death. HCC is usually based on chronic liver disease, mainly including chronic hepatitis C virus infection or chronic hepatitis B virus (HBV) infection. Objective The objective of the study was to evaluate the impact of the nucleos(t)ide analog (NA) use on the prognosis of patients with HBV-related small hepatocellular carcinomas (HBV-SHCC). Methods In this retrospective study, there were 134 patients who had been treated with long-term NA before SHCC diagnosis as NA-experienced group, 43 patients received NA-naïve treatment after SHCC diagnosis as NA-naïve group, and 15 patients who did not receive NA treatment as untreated group. Among these patients, some patients underwent surgical resection and others with local recurrence were treated with transarterial chemoembolization (TACE), TACE-percutaneous microwave coagulation therapy or TACE alone. The Kaplan-Meier and Cox-proportional hazard model were used to calculate the survival analysis. Results The data showed that 1-year, 3-year, 5-year overall survival rate of HBV-SHCC patients in NA-experienced group were 90.27%, 90.69%, 65%, NA-naïve group were 70.81%, 73.95%, 47.39%, and untreated group were 54.96%, 40.44%, 47.39%, respectively (Log-rank, P=0.031). The median survival time of HBV-SHCC patients treated with adefovir dipivoxil (ADV) or LAM+ADV has the longest survival time. Patients who have received rescue treatment after viral breakthrough or gotten maintained viral response had longer survival times than those who have not received rescue treatment after viral breakthrough or non-response. Compared with timely rescue treatment, viral breakthrough (hazard ratio=3.624, 95% CI, 1.035-12.687, P=0.044) was an independent risk factor for HBV-SHCC patients with Cox-proportional hazard model. For these patients conforming to NA-treatment indications, commencement of NA treatment should be given even after HBV-SHCC diagnosis. Moreover, HBV-SHCC patients who were suffering from virus break through should be treated timely rescue therapy even if their liver function was normal. Conclusion SHCC patients treated with low drug resistance barrier drugs may not change the treatment regimen if they have gotten virological response.
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Affiliation(s)
- Yanyan Wei
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.,Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China
| | - Yongxiang Yi
- Department of Hepatobiliary Surgeon, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Chen Tao
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.,Department of Hepatobiliary Surgeon, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Wei Ye
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.,Department of Hepatobiliary Surgeon, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Wei Zhao
- Department of Infectious Diseases, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.,Department of Hepatobiliary Surgeon, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
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Zhang Y, Li W, Liu Z, Ye J, Zou G, Zhang Z, Li J. Combination therapy based on pegylated interferon alfa improves the therapeutic response of patients with chronic hepatitis B who exhibit high levels of hepatitis B e-antigen at 24 weeks: A retrospective observational study. Medicine (Baltimore) 2019; 98:e17022. [PMID: 31490387 PMCID: PMC6738969 DOI: 10.1097/md.0000000000017022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 07/31/2019] [Accepted: 08/11/2019] [Indexed: 12/14/2022] Open
Abstract
Pegylated interferon alpha (PEG-IFN-α) is a first-line treatment for patients with chronic hepatitis B (CHB), but its efficacy varies from individual to individual. Early discrimination between responder and non-responder patients is important for optimal clinical management. In addition, low therapeutic efficacy is still a major issue; thus, treatment timing should be optimized.We reviewed our experience with hepatitis B e-antigen (HBeAg)-positive patients treated with PEG-IFN-α, alone or in combination with nucleoside analogues (NAs), from 2009 through 2014. Collected data included both general characteristics of 113 patients and laboratory data at baseline and at treatment weeks 12, 24, 52, and 76. The endpoint was HBeAg seroconversion at week 76.A total of 113 patients with changed to or start of NAs therapy were included in this study. At the end of treatment, 44 (38.9%) patients exhibited HBeAg seroconversion. Patients with HBeAg seroconversion had lower baseline HBeAg (475.5 vs 751.7; P = .007). The incidence of HBeAg seroconversion was significantly higher among patients with HBeAg ≤ 500 signal-to-cutoff ratio (S/CO) (OR = 2.60, 95% CI: 1.16-5.83, P = .02) at baseline, HBeAg S/CO ≤ 20 (OR = 3.37, 95% CI: 1.47-7.73, P = .003), or a higher than 10-fold HBeAg drop (OR = 3.55, 95% CI: 1.50-8.37, P = .003) at week 12 or HBeAg ≤ 15 S/CO (OR = 10.35, 95% CI: 4.09-26.20, P < .001) at week 24. Subgroup analyses demonstrated that in patients with HBeAg >20 S/CO at 24 weeks, the addition of NAs treatment may increase HBeAg seroconversion (23.3% vs 0%, P = .03).HBeAg levels had an impact on the rate of serological conversion in CHB patients receiving PEG-IFN-based treatment. Combination therapy with NAs should be considered in CHB patients maintaining a high HBeAg level after 24 weeks of PEG-IFN monotherapy.
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Affiliation(s)
- Yafei Zhang
- Department of Infectious Diseases, The First Affiliated Hospital, Anhui Medical University
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Wei Li
- Department of Liver Diseases, Fuyang Second People's Hospital, Fuyang, China
| | - Zhongping Liu
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Jun Ye
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Guizhou Zou
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital, Anhui Medical University, Hefei
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital, Anhui Medical University
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Xu X, Chen J, Wei Q, Liu ZK, Yang Z, Zhang M, Wang GY, Gao J, Yang ZX, Guo WY, Xing TH, Shao Z, Xie QF, Zheng SS. Clinical practice guidelines on liver transplantation for hepatocellular carcinoma in China (2018 edition). Hepatobiliary Pancreat Dis Int 2019; 18:307-312. [PMID: 31279679 DOI: 10.1016/j.hbpd.2019.06.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/11/2019] [Indexed: 02/05/2023]
Affiliation(s)
- Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Jun Chen
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhi-Kun Liu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhe Yang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ming Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guo-Ying Wang
- Department of Hepatic Surgery, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Zhao-Xu Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an 710032, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Tong-Hai Xing
- General Surgery Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China
| | - Zhou Shao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qin-Fen Xie
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310004, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Torresi J, Tran BM, Christiansen D, Earnest-Silveira L, Schwab RHM, Vincan E. HBV-related hepatocarcinogenesis: the role of signalling pathways and innovative ex vivo research models. BMC Cancer 2019; 19:707. [PMID: 31319796 PMCID: PMC6637598 DOI: 10.1186/s12885-019-5916-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 07/09/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is the leading cause of liver cancer, but the mechanisms by which HBV causes liver cancer are poorly understood and chemotherapeutic strategies to cure liver cancer are not available. A better understanding of how HBV requisitions cellular components in the liver will identify novel therapeutic targets for HBV associated hepatocellular carcinoma (HCC). MAIN BODY The development of HCC involves deregulation in several cellular signalling pathways including Wnt/FZD/β-catenin, PI3K/Akt/mTOR, IRS1/IGF, and Ras/Raf/MAPK. HBV is known to dysregulate several hepatocyte pathways and cell cycle regulation resulting in HCC development. A number of these HBV induced changes are also mediated through the Wnt/FZD/β-catenin pathway. The lack of a suitable human liver model for the study of HBV has hampered research into understanding pathogenesis of HBV. Primary human hepatocytes provide one option; however, these cells are prone to losing their hepatic functionality and their ability to support HBV replication. Another approach involves induced-pluripotent stem (iPS) cell-derived hepatocytes. However, iPS technology relies on retroviruses or lentiviruses for effective gene delivery and pose the risk of activating a range of oncogenes. Liver organoids developed from patient-derived liver tissues provide a significant advance in HCC research. Liver organoids retain the characteristics of their original tissue, undergo unlimited expansion, can be differentiated into mature hepatocytes and are susceptible to natural infection with HBV. CONCLUSION By utilizing new ex vivo techniques like liver organoids it will become possible to develop improved and personalized therapeutic approaches that will improve HCC outcomes and potentially lead to a cure for HBV.
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Affiliation(s)
- Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Bang Manh Tran
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Dale Christiansen
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Linda Earnest-Silveira
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Renate Hilda Marianne Schwab
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Elizabeth Vincan
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6845 Australia
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Di Bisceglie AM, King WC, Lisker-Melman M, Khalili M, Belle SH, Feld JJ, Ghany MG, Janssen HL, Lau D, Lee WM, Ling SC, Cooper S, Rosenthal P, Schwarz KB, Sterling RK, Teckman JH, Terrault N. Age, race and viral genotype are associated with the prevalence of hepatitis B e antigen in children and adults with chronic hepatitis B. J Viral Hepat 2019; 26:856-865. [PMID: 30974509 PMCID: PMC6592737 DOI: 10.1111/jvh.13104] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/07/2019] [Accepted: 03/15/2019] [Indexed: 12/23/2022]
Abstract
Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy.
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Affiliation(s)
| | - Wendy C. King
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh
| | | | - Mandana Khalili
- University of California at San Francisco, Toronto General Hospital, University of Toronto
| | - Steven H. Belle
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh
| | - Jordan J. Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto
| | - Marc G. Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| | - Harry L.A. Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto
| | - Daryl Lau
- Beth Israel Deaconess Medical Center
| | | | - Simon C. Ling
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto
| | | | - Philip Rosenthal
- University of California at San Francisco, Toronto General Hospital, University of Toronto
| | | | | | | | - Norah Terrault
- University of California at San Francisco, Toronto General Hospital, University of Toronto
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Zhang Z, Zhou Y, Yang J, Hu K, Huang Y. The effectiveness of TDF versus ETV on incidence of HCC in CHB patients: a meta analysis. BMC Cancer 2019; 19:511. [PMID: 31142283 PMCID: PMC6542001 DOI: 10.1186/s12885-019-5735-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 05/21/2019] [Indexed: 02/07/2023] Open
Abstract
Background It has been proved that nucleos(t) ide analogues (NAs) therapy could improve underlying liver disease and reduce the incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the difference of effectiveness in reducing HCC occurrence between tenofovir (TDF) and enticavir (ETV), two first-line NAs drugs, is still little known. This meta analysis aims to assess the efficacy in reducing incidence of HCC comparing tenofovir monotherapy with entecavir monotherapy among chronic hepatitis B (CHB) patients by analyzing their long-term clinical outcomes. Methods Databases including PubMed, Embase, Cochrane Central Register of Controlled Trial, and ISI Web of Science were fully investigated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For the included articles, two of the authors independently extracted and confirmed relevant data. Review Manager software (RevMan 5.3) was using for meta analysis. Results Seven articles with 3698 patients were finally included in this research, 1574 in tenofovir group and 2124 in entecavir group. For meta analysis, the incidence of HCC was significantly lower among the tenofovir group than entecavir group [rate ratio (95% CI) of 0.66 (0.49, 0.89), P = 0.008], while there was no statistical significance in incidence of death or transplantation [rate ratio (95% CI) of 0.78 (0.55, 1.13), P = 0.19], encephalopathy [risk ratio (95% CI) of 0.72 (0.45, 1.13), P = 0.15] or variceal bleeding [risk ratio (95% CI) of 0.71 (0.34, 1.50), P = 0.37] between the two groups. Conclusion There is a better effect of tenofovir in reducing HCC incidence than entecavir, which indicates tenofovir should be used more widely while treating chronic hepatitis B patients. However before applying, randomized controlled trial and large prospective cohort study should be performed in the future. Electronic supplementary material The online version of this article (10.1186/s12885-019-5735-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zeyu Zhang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yufan Zhou
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiajin Yang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Kuan Hu
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yun Huang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Endeshaw M, Hallowell BD, Razzaghi H, Senkomago V, McKenna MT, Saraiya M. Trends in liver cancer mortality in the United States: Dual burden among foreign- and US-born persons. Cancer 2019; 125:726-734. [PMID: 30480828 PMCID: PMC6681907 DOI: 10.1002/cncr.31869] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/17/2018] [Accepted: 10/23/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Since the mid-1980s, the burden of liver cancer in the United States has doubled, with 31,411 new cases and 24,698 deaths occurring in 2014. Foreign-born individuals may be more likely to die of liver cancer than individuals in the general US-born population because of higher rates of hepatitis B infection, a low socioeconomic position, and language barriers that limit the receipt of early cancer detection and effective treatment. METHODS To determine whether liver cancer mortality rates were higher among foreign-born individuals versus US-born individuals in the United States, population-based cancer mortality data were obtained from the National Center for Health Statistics of the Centers for Disease Control and Prevention. Annual population estimates were obtained from the US Census Bureau's American Community Survey. Age-adjusted mortality rates and rate ratios (RRs) for liver cancer stratified by birth place were calculated, and the average annual percent change (AAPC) was used to evaluate trends. RESULTS A total of 198,557 deaths from liver and intrahepatic bile duct cancer were recorded during 2005-2014, and 16% occurred among foreign-born individuals. Overall, foreign-born individuals had a 24% higher risk of liver cancer mortality than US-born individuals (RR, 1.24; 95% confidence interval [CI], 1.22-1.25). Foreign-born individuals did not have any significant changes in liver cancer mortality rates overall, but among US-born individuals, liver cancer mortality rates significantly increased (AAPC, 2.7; 95% CI, 2.1-3.3). CONCLUSIONS Efforts that address the major risk factors for liver cancer are needed to help to alleviate the health disparities observed among foreign-born individuals and reverse the increasing trend observed in the US-born population.
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Affiliation(s)
| | | | - Hilda Razzaghi
- Centers for Disease Control and Prevention, Atlanta, Georgia
| | | | | | - Mona Saraiya
- Centers for Disease Control and Prevention, Atlanta, Georgia
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Xu M, Zhou Z, Xu R, Zhang H, Lin N, Zhong Y. Antiviral therapy predicts the outcomes following resection of hepatocellular carcinoma in patients negative for HBV DNA: a propensity score matching analysis. World J Surg Oncol 2019; 17:45. [PMID: 30823932 PMCID: PMC6397498 DOI: 10.1186/s12957-019-1577-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 02/11/2019] [Indexed: 02/07/2023] Open
Abstract
Background The effect of antiviral therapy (AVT) on clinical outcomes in patients with hepatocellular carcinoma (HCC) who are seronegative for hepatitis B virus (HBV), defined as HBV DNA < 100 IU/ml prior to surgical resection, is unknown. The main purpose of this study was to evaluate the possible value of AVT in this cohort of patients. Methods From January 2006 to January 2013, 161 HCC patients with positive serum tests for HBV surface antigen (HBsAg) but negative tests for HBV DNA who had undergone hepatectomy were included and analyzed. Propensity score matching (PSM) was used to balance the heterogeneity in baseline characteristics. Results All patients were divided into the following two groups: the AVT group (n = 73, 45.34%) and the non-AVT group (n = 88, 54.66%). HBV reactivation occurred in 20 patients in the non-AVT group (22.73%) but in only 2 patients in the AVT group (2.74%, p < 0.001). After PSM, the 1-, 2-, and 3-year recurrence-free survival (RFS) rates in the AVT group and the non-AVT group were 78.38%, 72.97%, and 62.16% and 81.08%, 72.97%, and 72.97%, respectively (p = 0.564); the 1-, 2-, and 3-year overall survival (OS) rates were 97.30%, 97.3%, and 91.89% and 94.59%, 94.59%, and 86.49% in the AVT group and non-AVT group, respectively (p = 0.447). Conclusions Antiviral therapy can reduce HBV reactivation but is not correlated with a significant increase in postoperative RFS and OS in HCC patients with HBV DNA levels < 100 IU/ml. Electronic supplementary material The online version of this article (10.1186/s12957-019-1577-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mingxing Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Zheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Ruiyun Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Huiling Zhang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
| | - Yuesi Zhong
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
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Zhao J, Wang J, Chai S, Zhang Y, Zhang W. Elevated lactate impairs the efficacy of antiviral treatment on post-hepatectomy survival for advanced stage hepatitis B virus - related hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2019; 43:67-76. [PMID: 30219693 DOI: 10.1016/j.clinre.2018.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/30/2018] [Accepted: 08/06/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Nucleoside and nucleotide analogues (NAs) have a risk of mitochondrial toxicity and then inducing the increase of lactate. We aim to evaluate the impact of lactate on the effects of NAs therapy in hepatitis B virus-related hepatocellular carcinoma (HCC) patients after curative liver resection. MATERIALS AND METHODS Five hundred and fifty-seven HBV-related HCC patients were divided into the treatment and control group according to whether they received NAs therapy or not. Perioperative and prognosis data were retrospectively reviewed. RESULTS The treatment group had a better overall survival rate (OS) than the control group (P = 0.017). The recurrence-free survival rate (RFS) did not significantly differ between the two groups (P = 0.174). NAs could improve the OS of early stage HCC patients (P = 0.028), as well as the OS of advanced stage HCC patients with low level of lactate in subgroup analysis stratified against the level of lactate (P = 0.037). Advanced stage HCC patients in the treatment group had a higher value of lactate than those in the control group (P = 0.024). Besides, advanced stage HCC patients had a higher value of lactate than early stage HCC patients in the treatment group (P < 0.001), as well as in the control group (P < 0.001). CONCLUSIONS NAs could improve the long-term outcomes of HBV-related HCC patients after curative liver resection. However, the improvement effect of NAs therapy is counteracted by the adverse effect of elevated lactate in advanced stage HBV-related HCC patients.
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Affiliation(s)
- Jianping Zhao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingjing Wang
- Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songshan Chai
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuxin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Mak LY, Seto WK, Fung J, Yuen MF. Novel developments of hepatitis B: treatment goals, agents and monitoring tools. Expert Rev Clin Pharmacol 2019; 12:109-120. [DOI: 10.1080/17512433.2019.1567327] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
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Nishida N, Kita R, Miyoshi K, Koda M, Iwai M, Suriawinata AA. Liver Tumors II: Malignant Tumors of the Liver. DIAGNOSIS OF LIVER DISEASE 2019:235-267. [DOI: 10.1007/978-981-13-6806-6_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Liu J, Zhang H, Xia Y, Yang T, Gao Y, Li J, Wu Y, Shen F. Impact of clinically significant portal hypertension on outcomes after partial hepatectomy for hepatocellular carcinoma: a systematic review and meta-analysis. HPB (Oxford) 2019; 21:1-13. [PMID: 30082213 DOI: 10.1016/j.hpb.2018.07.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/29/2018] [Accepted: 07/02/2018] [Indexed: 01/27/2023]
Abstract
BACKGROUND Whether clinically significant portal hypertension (CSPH) is a contraindication of partial hepatectomy for patients with hepatocellular carcinoma (HCC) remains controversial. The aim was to assess the impact of CSPH on surgical morbidity, mortality and long-term survival of HCC patients who underwent partial hepatectomy. METHODS A systematic review and meta-analysis was conducted through analyzing the data published before October 2016 on outcomes following partial hepatectomy for HCC patients with CSPH from the Medline, Embase and CENTRAL databases and related literature. RESULTS A total of 16 studies involving 4029 patients met the inclusion criteria. HCC patients with CSPH had increased incidences of severe postoperative complications (pooled odds ratio [OR]: 1.66; 95% CI: 1.31-2.10), surgical mortality (2.56, 1.77-3.70) and 5-year mortality (1.29, 1.11-1.50) compared with patients without CSPH. Subgroup analysis suggested that CSPH had no impact on peri-operative mortality and long-term survival for European HCC patients whose CSPH was diagnosed by the standard surrogate criteria (1.95, 0.96-3.96; 1.24, 0.98-1.55). CONCLUSIONS CSPH had a negative impact on short- and long-term prognoses for HCC patients undergoing partial hepatectomy. However, CSPH did not affect the prognoses in a subgroup of European HCC patients whose CSPH was diagnosed by the standard surrogate criteria.
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Affiliation(s)
- Jianwei Liu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Zhang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tian Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yuzhen Gao
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun Li
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yeye Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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