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Cairoli V, Valle-Millares D, Ryan P, Dominguez L, Martín-Carbonero L, De los Santos I, De Matteo E, Ameigeiras B, De Sousa M, Briz V, Preciado MV, Fernández-Rodriguez A, Valva P. Extracellular vesicles derived microRNAs as non-invasive markers of liver fibrosis in chronically infected HCV patients: a pilot study. Noncoding RNA Res 2025; 12:132-140. [PMID: 40176849 PMCID: PMC11964596 DOI: 10.1016/j.ncrna.2025.03.004] [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: 06/27/2024] [Revised: 12/08/2024] [Accepted: 03/04/2025] [Indexed: 04/05/2025] Open
Abstract
Extracellular vesicles (EVs) are an increasingly promising tool for liquid biopsy in liver diseases. Hepatitis C Virus (HCV) infection, alone or together with Human Immunodeficiency Virus (HIV) infection significantly impacts on the microRNA (miRNA) EVs content resembling chronic hepatitis C (CHC) progression. The objective of the study was to delve into the intricate EVs-miRNA profiles in CHC patients with different liver fibrosis stages, aiming to pinpoint non-invasive markers capable of distinguishing significant fibrosis. Plasma EV-miRNAs from 50 CHC patients (HCV+ and HCV+/HIV+) stratified in no significant (F < 2) and significant (F ≥ 2) fibrosis, were massively sequenced. General linear models (GLM) were used to identify significantly differential expressed (SDE) miRNAs according to liver fibrosis stages (F ≥ 2 and F < 2). Dysregulated biological pathways were subsequently analyzed in silico for the following groups: i) all patients; ii) HCV+; and iii) HCV+/HIV+. Multiple-ordered logistic regression analysis was performed to develop a score to identify F ≥ 2 cases. The diagnostic potential of both the SDE miRNAs and the developed score was assessed using ROC curve analysis. With respect to all CHC patients, two SDE miRNAs (hsa-miR-122-5p and hsa-miR-92a-3p) were identified which regulate genes related to cytoskeleton organization. Regarding their diagnostic performance to discriminate F ≥ 2, both miRNAs individually demonstrated acceptable diagnostic values. However, their combined use in a new score enhanced their diagnostic performance (AUROC = 0.833). In the HCV+ subgroup, 8 SDE miRNAs (hsa-miR-122-5p, hsa-miR-320c, hsa-miR-3615, hsa-miR-320a-3p, hsa-miR-374b-5p, hsa-let-7a-3p, hsa-miR-199a-5p, hsa-miR-142-5p), which regulate macrophage activity and cell growth/death regulation, were recognized. Among them, hsa-miR-3615 displayed the highest diagnostic performance to discriminate F ≥ 2 (AUROC = 0.936). With respect to HCV+/HIV+, 18 SDE miRNAs (hsa-miR-4508, hsa-miR-122-5p, hsa-miR-451a, hsa-miR-1290, hsa-miR-1246, hsa-miR-107, hsa-miR-15b-5p, hsa-miR-194-5p, hsa-miR-22-5p, hsa-miR-20b-5p, hsa-miR-142-5p, hsa-miR-328-3p, hsa-miR-335-3p, hsa-miR-125a-5p, hsa-miR-423-3p, hsa-let-7d-3p, hsa-miR-128-3p, hsa-miR-10a-5p) were recognized that regulate RNA silencing processes. In this case, hsa-miR-423-3p and hsa-miR-128-3p showed outstanding diagnostic performances (AUROC > 0.900). Distinct EVs-miRNA profiles were identified in patients with varying liver fibrosis stages, both in the overall CHC cohort and within HCV+ and HCV+/HIV+ subgroups. These specific miRNA signatures would allow the elucidation of potential mechanisms involved in clinical evolution and identification of specific biomarkers of unfavorable progression, plausible to be used in a diagnostic panel. Furthermore, the developed score demonstrates the ability to discriminate within the CHC group those individuals with significant fibrosis regardless of their HIV infection status.
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Affiliation(s)
- Victoria Cairoli
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
| | - Daniel Valle-Millares
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Pablo Ryan
- Infectious Diseases Department, Internal Medicine Department HIV/Hepatitis, Infanta Leonor University Hospital, 28031, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Lourdes Dominguez
- HIV Unit, Internal Medicine Department, Research Institute of the Hospital 12 de Octubre (imas12), 28041, Madrid, Spain
| | - Luz Martín-Carbonero
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
- Infectious Diseases Unit, Internal Medicine Department, La Paz University Hospital, IdiPAZ, 28046, Madrid, Spain
| | - Ignacio De los Santos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
- Infectious Diseases Unit, Internal Medicine Department, La Princesa University Hospital, 28006, Madrid, Spain
| | - Elena De Matteo
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
| | - Beatriz Ameigeiras
- Liver Unit, Ramos Mejía Hospital, C1221ADC CABA, Buenos Aires, Argentina
| | - Marcela De Sousa
- Liver Unit, Ramos Mejía Hospital, C1221ADC CABA, Buenos Aires, Argentina
| | - Verónica Briz
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
- Viral Hepatitis Reference and Research Laboratory, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28222, Madrid, Spain
| | - María V. Preciado
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
| | - Amanda Fernández-Rodriguez
- Unit of Viral Infection and Immunity, National Center for Microbiology (CNM), Health Institute Carlos III (ISCIII), Majadahonda, 28222, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28222, Madrid, Spain
| | - Pamela Valva
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children's Hospital, C1425EFD CABA, Buenos Aires, Argentina
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Choi WJ, Ivanics T, Claasen M, Magyar CTJ, Li Z, Tabrizian P, Rocha C, Myers B, O'Kane GM, Reig M, Ferrer Fàbrega J, Holgin V, Parikh ND, Pillai A, Hunold TM, Vogel A, Patel MS, Singal AG, Tadros M, Feld JJ, Hansen B, Sapisochin G. Direct-acting antivirals lower mortality and recurrence in HCV-related hepatocellular carcinoma post liver resection: A multicenter international study. Surgery 2025; 183:109396. [PMID: 40334495 DOI: 10.1016/j.surg.2025.109396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/31/2025] [Accepted: 04/03/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND The impact of treatment on hepatitis C virus with direct-acting antivirals on 90-day postoperative outcomes, overall survival, and recurrence-free survival in patients after liver resection for hepatocellular carcinoma is unknown. METHODS We conducted a multicenter retrospective study. Adults who underwent liver resection for hepatitis C virus-related hepatocellular carcinoma between January 2000 and December 2018 were included from 7 international institutions. Groups included direct-acting antiviral treated, non-direct-acting antiviral treated, and untreated hepatitis C virus infection. We used a multivariable model to evaluate the association between receipt of preoperative direct-acting antivirals and 90-day postoperative major complications (Clavien-Dindo class ≥III). RESULTS We identified 738 patients, including 206 (28%) direct-acting antiviral treated, 241 (33%) non-direct-acting antiviral treated, and 291 (39%) untreated patients. The sustained virologic response rate was 92% in the direct-acting antiviral and 71% in the non-direct-acting antiviral treatment groups. The median follow-up was 7.6 years (95% confidence interval 6.1, 8.6) after surgery for the entire cohort. Patients who received direct-acting antiviral therapy had better 5-year overall and recurrence-free survival than those without antiviral therapy (adjusted hazard ratio [95% confidence interval]: 0.26 [0.19, 0.35] and 0.52 [0.43, 0.64], respectively). Patients who received direct-acting antiviral therapy had better 5-year overall and recurrence-free survival than those who received non-direct-acting antiviral therapy (adjusted hazard ratio [95% confidence interval]: 0.49 [0.36, 0.66] and 0.78 [0.63, 0.96], respectively). There was no significant association between preoperative direct-acting antiviral therapy and 90-day postoperative major complications (adjusted odds ratio 0.34, 95% confidence interval 0.08, 1.01). CONCLUSION Direct-acting antiviral therapy is associated with improved 5-year overall and recurrence-free survival, without significantly increased risk of 90-day postoperative complications, in patients undergoing liver resection for hepatitis C virus-related hepatocellular carcinoma.
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Affiliation(s)
- Woo Jin Choi
- Department of Surgery, University of Toronto, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Tommy Ivanics
- University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Surgery, Henry Ford Hospital, Detroit, MI; Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Marco Claasen
- University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Christian T J Magyar
- University Health Network, HPB Oncology Research, Toronto, ON, Canada; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Zhihao Li
- University Health Network, HPB Oncology Research, Toronto, ON, Canada
| | - Parissa Tabrizian
- Department of Liver Transplantation and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Chiara Rocha
- Department of Liver Transplantation and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Bryan Myers
- Department of Liver Transplantation and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Grainne M O'Kane
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; St. Vincent's University Hospital and University College Dublin, Dublin, Ireland
| | - Maria Reig
- Department of Surgery, ICMDM, IDIBAPS, CIBEREHD, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Joana Ferrer Fàbrega
- Department of Surgery, ICMDM, IDIBAPS, CIBEREHD, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Victor Holgin
- Department of Surgery, ICMDM, IDIBAPS, CIBEREHD, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Neehar D Parikh
- Department of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Anjana Pillai
- Department of Gastroenterology, University of Chicago Medical Center, Chicago, IL
| | - Thomas M Hunold
- Department of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Arndt Vogel
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Toronto Center for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Madhukar S Patel
- Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Center, Dallas, TX
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Center, Dallas, TX
| | - Meena Tadros
- Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Center, Dallas, TX
| | - Jordan J Feld
- Department of Gastroenterology, Toronto Center for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Bettina Hansen
- Department of Gastroenterology, Toronto Center for Liver Disease, University Health Network, Toronto, ON, Canada; Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands
| | - Gonzalo Sapisochin
- Department of Surgery, University of Toronto, Toronto, ON, Canada; University Health Network, HPB Oncology Research, Toronto, ON, Canada.
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Zhuo E, Yang W, Wang Y, Tang Y, Wang W, Zhou L, Chen Y, Li P, Chen B, Gao W, Liu W. Global trends in machine learning applied to clinical research in liver cancer: Bibliometric and visualization analysis (2001-2024). Medicine (Baltimore) 2024; 103:e40790. [PMID: 39654222 PMCID: PMC11631000 DOI: 10.1097/md.0000000000040790] [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: 09/12/2024] [Revised: 11/09/2024] [Accepted: 11/14/2024] [Indexed: 12/12/2024] Open
Abstract
This study explores the intersection of liver cancer and machine learning through bibliometric analysis. The aim is to identify highly cited papers in the field and examine the current research landscape, highlighting emerging trends and key areas of focus in liver cancer and machine learning. By analyzing citation patterns, this study sheds light on the evolving role of machine learning in liver cancer research and its potential for future advancements.
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Affiliation(s)
- Enba Zhuo
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenzhi Yang
- First Clinical College, Anhui Medical University, Hefei, China
| | - Yafen Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yanchao Tang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wanrong Wang
- First Clinical College, Anhui Medical University, Hefei, China
| | - Lingyan Zhou
- First Clinical College, Anhui Medical University, Hefei, China
| | - Yanjun Chen
- First Clinical College, Anhui Medical University, Hefei, China
| | - Pengman Li
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bangjie Chen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Weimin Gao
- First Clinical College, Anhui Medical University, Hefei, China
| | - Wang Liu
- Department of General Surgery, Sanya Central Hospital (The Third People’s Hospital of Hainan Province), Sanya, China
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Chow VYS, Cheung WI. Evaluation of patients treated with direct-acting anti-viral therapy for chronic hepatitis C and their risk of hepatocellular carcinoma in Hong Kong. BMC Gastroenterol 2024; 24:49. [PMID: 38273255 PMCID: PMC10811862 DOI: 10.1186/s12876-023-03099-2] [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: 09/14/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND & AIM To evaluate the risk of early hepatocellular carcinoma (HCC) in chronic hepatitis C patients treated with direct-acting antivirals (DAAs) in Hong Kong, as it has not been studied before in this locality. METHODS Three hundred thirty-three consecutive chronic hepatitis C patients treated with DAAs from two hospitals over the past 6 years were identified. Kaplan-Meier method was used to calculate cumulative HCC incidence. Cox regression was used to identify factors associated with HCC development. RESULTS During a median follow-up of 23.4 months after DAA started, 15 (5.4%, 95% CI 3.3-8.7%) out of 279 total included patients developed HCC. The overall sustained virological response (SVR) rate was 98.9%. The 1-year cumulative incidence for de-novo HCC and HCC recurrence were 0.8 and 30.9%, respectively (log-rank test p < 0.001). The 1-year cumulative HCC incidence for patients without and with cirrhosis were 0.7 and 5.1%, respectively (log-rank test p = 0.036). Univariate analysis showed that significant factors associated with HCC after DAA were: history of treated HCC, cirrhosis, evidence of portal hypertension, higher AFP at the start or end of DAA therapy, higher bilirubin, lower platelets, lower albumin, and older age. From receiver operating characteristic curve analysis, the optimal cut-off level of AFP for predicting HCC was 10.5 ng/mL at the start and 5.6 ng/mL at the end of DAA therapy. CONCLUSIONS The risk of early HCC recurrence remains high despite achieving SVR following DAA therapy, whereas the risk of early de-novo HCC occurence is low. AFP levels, both at the start and end of DAA therapy, can be useful in stratifying risks of HCC development.
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Stauffer W, Bobardt M, Ure D, Foster R, Gallay P. The Cyclophilin Inhibitor Rencofilstat Decreases HCV-Induced Hepatocellular Carcinoma Independently of Its Antiviral Activity. Viruses 2023; 15:2099. [PMID: 37896876 PMCID: PMC10612079 DOI: 10.3390/v15102099] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/07/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypIs) represent such new drugs. We demonstrate that the nonimmunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we show that the HCV infection of humanized mice results in the progressive development of HCC. This is true for the four genotypes tested (1 to 4). Remarkably, we demonstrate that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks after infection when HCC is well established. Importantly, we show that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC, while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.
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Affiliation(s)
- Winston Stauffer
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; (W.S.); (M.B.)
| | - Michael Bobardt
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; (W.S.); (M.B.)
| | - Daren Ure
- Hepion Pharmaceuticals Inc., Edison, NJ 08837, USA; (D.U.); (R.F.)
| | - Robert Foster
- Hepion Pharmaceuticals Inc., Edison, NJ 08837, USA; (D.U.); (R.F.)
| | - Philippe Gallay
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; (W.S.); (M.B.)
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Stauffer W, Bobardt M, Ure D, Foster R, Gallay P. The Cyclophilin Inhibitor Rencofilstat Decreases HCV-induced Hepatocellular Carcinoma Independently of Its Antiviral Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553982. [PMID: 37645728 PMCID: PMC10462172 DOI: 10.1101/2023.08.19.553982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypI) represent such new drugs. We demonstrated that the non-immunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we showed that HCV infection of humanized mice results in the progressive development of HCC. This was true for four genotypes tested (1 to 4). Remarkably, we demonstrated that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks post-infection when HCC is well established. Importantly, we showed that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.
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Affiliation(s)
- Winston Stauffer
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Michael Bobardt
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Daren Ure
- Hepion Pharmaceuticals Inc., Edison, New Jersey, USA
| | - Robert Foster
- Hepion Pharmaceuticals Inc., Edison, New Jersey, USA
| | - Philippe Gallay
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, USA
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Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma:Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol 2023; 93:20-35. [PMID: 37149203 DOI: 10.1016/j.semcancer.2023.04.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is estimated to be the third leading cause of cancer-related mortality and is characterized by low survival rates. Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of HCC, whose rates are increasing, owing to the increasing prevalence of NAFLD. The pathogenesis of NAFLD-associated HCC is multifactorial: insulin resistance, obesity, diabetes and the low-grade hepatic inflammation, which characterizes NAFLD, seem to play key roles in the development and progression of HCC. The diagnosis of NAFLD-associated HCC is based on imaging in the presence of liver cirrhosis, preferably computerized tomography or magnetic resonance imaging, but liver biopsy for histological confirmation is usually required in the absence of liver cirrhosis. Some preventive measures have been recommended for NAFLD-associated HCC, including weight loss, cessation of even moderate alcohol drinking and smoking, as well as the use of metformin, statins and aspirin. However, these preventive measures are mainly based on observational studies, thus they need validation in trials of different design before introducing in clinical practice. The treatment of NAFLD should be tailored on an individual basis and should be ideally determined by a multidisciplinary team. In the last two decades, new medications, including tyrosine kinase inhibitors and immune checkpoints inhibitors, have improved the survival of patients with advanced HCC, but trials specifically designed for patients with NAFLD-associated HCC are scarce. The aim of this review was to overview evidence on the epidemiology and pathophysiology of NAFLD-associated HCC, then to comment on imaging tools for its appropriate screening and diagnosis, and finally to critically summarize the currently available options for its prevention and treatment.
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Affiliation(s)
- Stergios A Polyzos
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
| | - Ilias D Vachliotis
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Chartampilas
- Department of Radiology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
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Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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Pinter M, Pinato DJ, Ramadori P, Heikenwalder M. NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy. Clin Cancer Res 2023; 29:513-520. [PMID: 36166660 PMCID: PMC9890137 DOI: 10.1158/1078-0432.ccr-21-1258] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/29/2022] [Accepted: 09/20/2022] [Indexed: 02/05/2023]
Abstract
The last 10 years have revolutionized our basic understanding of nonalcoholic fatty liver disease and consequent liver cancer. It has become clear that several innate and adaptive immune cells play an important role in initiating, maintaining, or exacerbating nonalcoholic steatohepatitis (NASH)-a disease that has been recently defined as autoaggressive. Despite improved disease management aimed at reducing the progression of fibrosis, NASH is set to become a leading cause for hepatocellular carcinoma (HCC). Preliminary data from preclinical studies suggest that immunotherapy efficacy may be reduced in NASH-related HCC compared with viral HCC; however, conclusive evidence supporting clinical translation of these findings is lacking. Comprehensive clinical and immunologic phenotyping of mechanisms linking NASH progression with carcinogenesis and therapeutic resistance is key to prevent progression to cirrhosis, improve monitoring and stratification of NASH according to predicted cancer risk, and ultimately increase survival of patients with NASH-HCC. In this review, we summarize the state of the art in the field of NASH and NASH-HCC with focus on immunobiology. We discuss preclinical and clinical findings underpinning NASH as an immunologically distinct pro-tumorigenic disease entity, and explore areas of potential therapeutic vulnerabilities in NASH-associated HCC.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - David J. Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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11
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Leal C, Strogoff-de-Matos J, Theodoro C, Teixeira R, Perez R, Guaraná T, de Tarso Pinto P, Guimarães T, Artimos S. Incidence and Risk Factors of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Treated with Direct-Acting Antivirals. Viruses 2023; 15:221. [PMID: 36680260 PMCID: PMC9863874 DOI: 10.3390/v15010221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Conflicting data regarding the incidence of hepatocellular carcinoma (HCC) after cure of HCV infection with direct-acting antivirals (DAAs) remains. We investigated the incidence and risk factors to HCC after treatment with DAAs followed up for five years. METHODS A total of 1075 HCV patients ≥ 18 years were treated with DAAs from 2015 to 2019 and followed until 2022. Ultrasonography was performed before DAAs and each 6 months thereafter. RESULTS Of the total, 51/1075 (4.7%) developed HCC in the median of 40 (IQR 25-58) months: 26/51 (51%) male, median age 60 (IQR 54-66) years, alpha-fetoprotein (AFP) 12.2 (IQR 6.1-18.8) ng/mL, 47/51 (92.1%) cirrhotic 78.7%, 8/51 (15.7%) without sustained virological response (SVR). Seventeen percent had non-characterized nodules before DAAs. Cumulative HCC incidence was 5.9% in 5 years. Overall incidence was 1.46/100 patient-years (PY) (95% CI = 1.09-1.91), being 2.31/100 PY (95% CI = 1.70-3.06), 0.45/100 PY (95% CI = 0.09-1.32) and 0.20/100 PY (95% CI 0.01-1.01) in METAVIR F4, F3 and F2, respectively, and the main risks to HCC were non-characterized nodule, cirrhosis, high AFP values and non-SVR. CONCLUSION HCV cure reduced risk for HCC, but it still occurred particularly in cirrhotic patients. Some risk factors can be identified to predict early HCC diagnosis.
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Affiliation(s)
- Cassia Leal
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
- Gastroenterology and Hepatology Unit, Antônio Pedro Universitary Hospital, Fluminense Federal University, Rio de Janeiro 24033-900, Brazil
| | - Jorge Strogoff-de-Matos
- Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro 24033-900, Brazil
| | - Carmem Theodoro
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
- Gastroenterology and Hepatology Unit, Antônio Pedro Universitary Hospital, Fluminense Federal University, Rio de Janeiro 24033-900, Brazil
| | - Rosangela Teixeira
- Departamento de Clínica Médica, Faculdade de Medicina, Instituto Alfa de Gastroenterologia Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil
- Hospital Felício Rocho, Belo Horizonte 30110-934, Brazil
| | - Renata Perez
- Hepatology Division, D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
- Hepatology Division, Federal University of Rio de Janeiro, Rio de Janeiro 21941913, Brazil
| | - Thais Guaraná
- Gastroenterology and Hepatology Unit, Antônio Pedro Universitary Hospital, Fluminense Federal University, Rio de Janeiro 24033-900, Brazil
| | - Paulo de Tarso Pinto
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
| | - Tatiana Guimarães
- Departamento Materno Infantil, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro 24033-900, Brazil
| | - Solange Artimos
- Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro 24033-900, Brazil
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2022 KLCA-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2022; 23:1126-1240. [PMID: 36447411 PMCID: PMC9747269 DOI: 10.3348/kjr.2022.0822] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022; 28:583-705. [PMID: 36263666 PMCID: PMC9597235 DOI: 10.3350/cmh.2022.0294] [Citation(s) in RCA: 174] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Korenaga M, Murata K, Izumi N, Tamaki N, Yokosuka O, Takehara T, Sakamoto N, Suda G, Nishiguchi S, Enomoto H, Ikeda F, Yanase M, Toyoda H, Genda T, Umemura T, Yatsuhashi H, Yamasaki K, Ide T, Toda N, Kanda T, Nirei K, Ueno Y, Haga H, Nishigaki Y, Nakane K, Omata M, Mochizuki H, Aoki Y, Imamura M, Kanto T, Mizokami M. No increased risk of hepatocellular carcinoma after eradication of hepatitis C virus by direct-acting antivirals, compared with interferon-based therapy. Glob Health Med 2022; 4:216-224. [PMID: 36119787 PMCID: PMC9420328 DOI: 10.35772/ghm.2022.01026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 07/19/2022] [Accepted: 07/28/2022] [Indexed: 06/15/2023]
Abstract
It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.
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Affiliation(s)
- Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kazumoto Murata
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Japan Red Cross Musashino Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Japan Red Cross Musashino Hospital, Tokyo, Japan
| | | | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shuhei Nishiguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirayuki Enomoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Fusao Ikeda
- Department of Gastroenterology, Okayama University Hospital, Okayama, Japan
| | - Mikio Yanase
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Takeji Umemura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan
| | - Kazumi Yamasaki
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Nobuo Toda
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yoichi Nishigaki
- Department of Gastroenterology, Gifu Municipal Hospital, Gifu, Japan
| | - Kunio Nakane
- Department of Gastroenterology, Akita City Hospital, Akita, Japan
| | - Masao Omata
- Genome Analysis Center, Yamanashi Prefecture Central Hospital, Yamanashi, Japan
| | - Hitoshi Mochizuki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yoshihiko Aoki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masatoshi Imamura
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
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Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [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: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
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Sanduzzi-Zamparelli M, Mariño Z, Lens S, Sapena V, Iserte G, Pla A, Granel N, Bartres C, Llarch N, Vilana R, Nuñez I, Darnell A, Belmonte E, García-Criado A, Díaz A, Muñoz-Martinez S, Ayuso C, Bianchi L, Fuster-Anglada C, Rimola J, Forner A, Torres F, Bruix J, Forns X, Reig M. Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules. J Hepatol 2022; 76:874-882. [PMID: 34856322 DOI: 10.1016/j.jhep.2021.11.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Recognition of non-characterized liver nodules (NCLN) prior to direct-acting antivirals (DAAs) is associated with increased hepatocellular carcinoma (HCC) risk in patients with HCV. The risk of HCC has not been defined in F3/F4 patients in whom NCLN have been ruled-out before starting DAAs and at sustained virological response (SVR). This study aimed to estimate HCC incidence in this population. METHODS We performed a prospective study including HCV-infected patients with F3/F4 fibrosis, without a history of HCC, and who achieved SVR after DAAs. Patients were only included if they had undergone ultrasound imaging that excluded the presence of HCC/NCLN within 30 days after SVR. All patients were evaluated every 6 months until developing primary liver cancer, death or withdrawal of informed consent. HCC incidence was expressed per 100 patient-years (/100PY). Adherence to screening program was calculated every 6 months for the first 48 months. RESULTS A total of 185 patients (63/122, F3/F4) were included. Among those with cirrhosis, 92% were Child-Pugh A and 42.7% had clinically significant portal hypertension (CSPH). Albumin-bilirubin score was 1 in 84.9% and 2 in 15.1% of patients, respectively. The median clinical and radiologic follow-up was 52.4 months and 48 months, respectively. Ten patients developed HCC: HCC incidence was 1.46/100PY (95% CI 0.79-2.71) in the whole cohort, 2.24/100PY (95% CI 1.21-4.17) in F4 only and 3.63/100PY (95% CI 1.95-6.74) in patients with CSPH. No HCC was registered in patients with F3. Median time between SVR and HCC occurrence was 28.1 months; 12 non-primary liver cancers were also identified. CONCLUSIONS Patients with cirrhosis without NCLN at SVR remain at risk of HCC development. The absence of HCC in patients with F3 reinforces their marginal cancer risk, but prospective studies are needed to exclude them from screening programs. LAY SUMMARY Patients with HCV-related cirrhosis, without non-characterized liver nodules at sustained virologic response, remain at risk of hepatocellular carcinoma despite viral cure. However, the cancer risk after successful direct-acting antiviral treatment is marginal in patients with F3 fibrosis without non-characterized liver nodules. If confirmed in larger prospective studies, current screening recommendations may need to be revisited in this group of patients.
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Affiliation(s)
- Marco Sanduzzi-Zamparelli
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Victor Sapena
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Gemma Iserte
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Anna Pla
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Núria Granel
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Concepció Bartres
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Neus Llarch
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Ramón Vilana
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Isabel Nuñez
- Radiology Department, Hospital Clinic of Barcelona, Spain
| | - Anna Darnell
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Ernest Belmonte
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Angeles García-Criado
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Alba Díaz
- BCLC Group. Department of Pathology, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Sergio Muñoz-Martinez
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Carmen Ayuso
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Luis Bianchi
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Carla Fuster-Anglada
- BCLC Group. Department of Pathology, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain
| | - Jordi Rimola
- BCLC Group. Radiology Department Hospital Clinic of Barcelona, CIBERehd, University of Barcelona, Spain
| | - Alejandro Forner
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Ferran Torres
- Medical Statistics Core Facility, IDIBAPS, Hospital Clinic of Barcelona, Spain; Biostatistics Unit, Faculty of Medicine, Universitat Autònoma of Barcelona, Barcelona, Spain
| | - Jordi Bruix
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Spain.
| | - Maria Reig
- BCLC Group. Liver Unit, Hospital Clinic of Barcelona, IDIBAPS. CIBERehd, University of Barcelona, Barcelona, Spain.
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El Kassas M, Eltabbakh M, Elbadry M, Tawheed A, Elbaz T. Establishing a research production line in real-life settings: the case of Hepatitis C management in a viral hepatitis specialized Egyptian center. Curr Med Res Opin 2022; 38:553-563. [PMID: 35118916 DOI: 10.1080/03007995.2022.2038489] [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: 10/12/2021] [Revised: 01/23/2022] [Accepted: 02/02/2022] [Indexed: 11/03/2022]
Abstract
Efforts toward eradicating the Hepatitis C virus (HCV) have advanced rapidly, due to the development of direct-acting antivirals (DAAs), especially with the appearance of pan-genotypic combinations. Real-world studies, in particular, have verified the efficacy and safety of DAA combinations documented in registration trials. This review documents the results of using DAA combinations in real-life settings in everyday clinical practice in Egypt, the country with the highest prevalence of HCV. The significant number of treated patients in Egypt, which exceeded four million allowed tremendous data about the results of HCV management in real-life settings for different treatment regimens and disease conditions. DAA combinations have resulted in high sustained virologic response rates (SVR12) and few adverse reactions in real-life settings. SVR12 rates ranged from 90% to 100%, depending on the combination of drugs used, the HCV genotype, and the stage of liver disease. Most adverse reactions reported in real-world settings were mild and resulted in treatment discontinuation in only a minority of cases. Data from real-life studies covered most aspects of HCV management that were lacking after initial approval studies. More research is needed to tailor treatment and produce generic HCV combinations to overcome the residual limitations of the currently available DAAs.
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Affiliation(s)
- Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Mohamed Eltabbakh
- Tropical Medicine department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Elbadry
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Ahmed Tawheed
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Tamer Elbaz
- Endemic Medicine and Hepatogastroenterology, Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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18
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The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma. Medicina (B Aires) 2022; 58:medicina58020259. [PMID: 35208582 PMCID: PMC8875284 DOI: 10.3390/medicina58020259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Objectives: The impact of direct-acting antiviral (DAA)-based regimens on the recurrence of hepatocellular carcinoma (HCC) after successful curative hepatectomy is controversial. Aims: This study aimed to assess the association between DAAs treatment and recurrence risk in HCC after resection. Materials and Methods: We retrospectively assessed 152 cases of early stage (BCLC stage 0/A) hepatitis C virus (HCV)-related HCC (HCV-HCC) that underwent resection with curative intent between 2001 and 2019 at Kaohsiung Chang Gung Memorial Hospital; 48 cases achieved a sustained virological response (SVR) by DAA, and 104 cases were not treated with any antiviral therapy (non-treatment group). Recurrence-free survival (RFS) following curative resection was analyzed by using the log-rank test and Kaplan–Meier method. A Cox proportional hazards model was used to analyze the factors that impacted RFS and OS. Results: Five patients (10.4%) experienced HCC recurrence after DAA therapy. The cumulative HCC recurrence rate was significantly lower in the DAA group than the non-treatment group (p < 0.001). Multivariate analysis revealed a significant difference in RFS between the non-treatment group and DAA group (p = 0.001; hazard ratio (HR), 4.978; 95% CI, 1.976–12.542); liver cirrhosis (p = 0.005; HR, 2.062; 95% CI, 1.247–3.410), microvascular invasion (p = 0.001; HR, 2.331; 95% CI, 1.408–3.860) and AFP > 15 ng/mL (p = 0.022; HR, 1.799; 95% CI, 1.089–2.970) were also independent factors for HCC recurrence. ALBI stage II/III (p = 0.005; HR, 3.249; 95% CI, 1.418–7.443) and microvascular invasion (p < 0.001; HR, 4.037 95% CI, 2.071–7.869) were independent factors for OS; no significant difference in OS was observed between the DAA and no DAA treatment groups. Conclusions: DAA treatment could reduce the risk of recurrence after curative treatment for early stage HCC.
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Celsa C, Stornello C, Giuffrida P, Giacchetto CM, Grova M, Rancatore G, Pitrone C, Di Marco V, Cammà C, Cabibbo G. Direct-acting antiviral agents and risk of Hepatocellular carcinoma: Critical appraisal of the evidence. Ann Hepatol 2022; 27 Suppl 1:100568. [PMID: 34699987 DOI: 10.1016/j.aohep.2021.100568] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals (DAAs) revolutionized the treatment of chronic HCV-related disease achieving high rates of sustained virological response (SVR), even in advanced cirrhosis, with modest contraindications and a low rate of adverse events. However, the risk of hepatocellular carcinoma (HCC) persists due to the underlying chronic liver disease, both in patients with and without history of HCC. Although some initial studies reported a presumptive high risk of HCC development after DAA therapy, more recent observational studies denied this hypothesis. The residual risk for HCC occurrence after HCV eradication seems being progressively reduced with time after SVR. Data on recurrence of HCC after DAA exposure in patients with previously treated carcinoma initially reported conflicting results too, this being also due to methodological issues in analysis of retrospective multicenter studies. Anyway, current evidence support the use of DAAs in HCV-HCC treated patients, without any higher risk of tumor recurrence linked to antiviral therapy. Less effort has been made to evaluate the efficacy of DAA therapy in patients with untreated active HCC and it has been questioned whether a lower rate of SVR would be obtained among patients with active HCC. Studies conducted in this perspective concluded that HCC status does not influence the likelihood to obtain SVR with DAAs, making DAAs appropriate in HCC-active patients. As far as survival is concerned, recent studies conducted in cirrhotic HCV-related early-stage HCC found that DAAs improved overall survival, a benefit probably due to the reduction of hepatic decompensation.
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Affiliation(s)
- Ciro Celsa
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy; Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Palermo, Sicilia, Italy
| | - Caterina Stornello
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Paolo Giuffrida
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Carmelo Marco Giacchetto
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Mauro Grova
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Gabriele Rancatore
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Concetta Pitrone
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy; Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Vito Di Marco
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Calogero Cammà
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
| | - Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
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20
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Lockart I, Hajarizadeh B, Buckley N, Davison S, Prakoso E, Levy MT, George J, Dore GJ, Danta M. All-cause hepatocellular carcinoma survival in the era of direct-acting antiviral therapy. J Gastroenterol Hepatol 2021; 36:3515-3523. [PMID: 34520088 DOI: 10.1111/jgh.15687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/20/2021] [Accepted: 09/04/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Hepatitis C virus (HCV) cure with direct-acting antiviral (DAA) therapy improves survival in patients with HCV-related hepatocellular carcinoma (HCC). We hypothesized that HCV-HCC survival has increased in the DAA era, more than other aetiologies of HCC. We aimed to evaluate survival following HCC diagnosis in the pre-DAA and DAA eras, across each aetiology of HCC. METHODS Patients with HCC at three tertiary referral hospitals were included retrospectively (January 2008 to December 2019). Patients were categorized as HCV-HCC, hepatitis B virus (HBV)-HCC, or non-viral HCC. For each aetiology, the risk of death following incident HCC among patients diagnosed in the DAA era (2015-2019) was compared with patients diagnosed in the pre-DAA era (2008-2014). RESULTS Among 1161 patients, there were 422 (36%) patients with HCV-HCC, 227 (20%) with HBV-HCC, and 512 (44%) with non-viral HCC. In adjusted analysis, the risk of death was lower in patients with HCV-HCC diagnosed in 2015-2019, compared with patients diagnosed in 2008-2014 (adjusted hazard ratio [aHR]: 0.68; 95% confidence interval [CI]: 0.52-0.89; P = 0.005). In contrast, there was no difference in the risk of death between time periods for patients with HBV-HCC (HR: 0.91; 95% CI: 0.64-1.29; P = 0.602) or non-viral HCC on adjusted analysis (aHR: 0.92; 95% CI: 0.74-1.15; P = 0.476). Although patients with HBV-HCC had better survival compared with patients with HCV-HCC in 2008-2014 (aHR: 0.74; 95% CI: 0.55-0.98; P = 0.037), this difference disappeared in 2015-2019 (aHR: 1.26; 95% CI: 0.90-1.77; P = 0.175). CONCLUSIONS Hepatitis C virus-related HCC survival has increased in the DAA era, whereas adjusted survival remained stable for HBV-HCC and non-viral HCC.
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Affiliation(s)
- Ian Lockart
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,St Vincent's Hospital, Sydney, New South Wales, Australia
| | | | - Niamh Buckley
- St Vincent's Hospital, Sydney, New South Wales, Australia
| | - Scott Davison
- Liverpool Hospital, Sydney, New South Wales, Australia.,South Western Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Emilia Prakoso
- Liverpool Hospital, Sydney, New South Wales, Australia.,Central Clinical School, The Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Miriam T Levy
- Liverpool Hospital, Sydney, New South Wales, Australia.,South Western Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Sydney, New South Wales, Australia
| | - Gregory J Dore
- St Vincent's Hospital, Sydney, New South Wales, Australia.,The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Mark Danta
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,St Vincent's Hospital, Sydney, New South Wales, Australia
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21
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Delgado Martínez C, Gómez-Rubio M, Gómez-Domínguez C. Is hepatitis C direct-acting antiviral therapy a risk factor for the development and recurrence of hepatocellular carcinoma? Narrative literature review and clinical practice recommendations. Ann Hepatol 2021; 21:100225. [PMID: 32687878 DOI: 10.1016/j.aohep.2020.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/26/2020] [Accepted: 05/31/2020] [Indexed: 02/04/2023]
Abstract
The development of direct-acting antivirals (DAAs) has been a turning point in chronic hepatitis C treatment. With an efficacy rate on viral eradication close to 100% and an excellent safety profile, they have replaced interferon-based treatments as first-line therapy for hepatitis C virus (HCV). Following the encouraging results observed during the first years with these treatments, new publications suggested an unexpectedly high incidence of hepatocellular carcinoma (HCC) in patients previously treated with DAAs as well as a higher HCC recurrence rate in them. The possible interaction between DAAs and HCC and its impact on HCC incidence and recurrence still remains controversial. The aim of the present work is to review the current state of the matter by analyzing studies that evaluate the association between chronic hepatitis C treatment with DAAs and the development of HCC either de novo or as a recurrence. Following this, clinical practice recommendations are done.
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Affiliation(s)
| | - Mariano Gómez-Rubio
- Division of Digestive Diseases, Hospital Universitario de Getafe, Madrid, Spain; Universidad Europea de Madrid, Madrid, Spain.
| | - Cecilia Gómez-Domínguez
- Division of Digestive Diseases, Hospital Universitario de Getafe, Madrid, Spain; Universidad Europea de Madrid, Madrid, Spain.
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22
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Rios DA, Casciato PC, Caldirola MS, Gaillard MI, Giadans C, Ameigeiras B, De Matteo EN, Preciado MV, Valva P. Chronic Hepatitis C Pathogenesis: Immune Response in the Liver Microenvironment and Peripheral Compartment. Front Cell Infect Microbiol 2021; 11:712105. [PMID: 34414132 PMCID: PMC8369367 DOI: 10.3389/fcimb.2021.712105] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C (CHC) pathogenic mechanisms as well as the participation of the immune response in the generation of liver damage are still a topic of interest. Here, we evaluated immune cell populations and cytokines in the liver and peripheral blood (PB) to elucidate their role in CHC pathogenesis. B, CTL, Th, Treg, Th1, Th17, and NK cell localization and frequency were evaluated on liver biopsies by immunohistochemistry, while frequency, differentiation, and functional status on PB were evaluated by flow cytometry. TNF-α, IL-23, IFN-γ, IL-1β, IL-6, IL-8, IL-17A, IL-21, IL-10, and TGF-β expression levels were quantified in fresh liver biopsy by RT-qPCR and in plasma by CBA/ELISA. Liver CTL and Th1 at the lobular area inversely correlated with viral load (r = −0.469, p =0.003 and r = −0.384, p = 0.040). Treg correlated with CTL and Th1 at the lobular area (r = 0.784, p < 0.0001; r = 0.436, p = 0.013). Th17 correlated with hepatic IL-8 (r = 0.52, p < 0.05), and both were higher in advanced fibrosis cases (Th17 p = 0.0312, IL-8 p = 0.009). Hepatic cytokines were higher in severe hepatitis cases (IL-1β p = 0.026, IL-23 p = 0.031, IL-8 p = 0.002, TGF-β, p= 0.037). Peripheral NK (p = 0.008) and NK dim (p = 0.018) were diminished, while NK bright (p = 0.025) was elevated in patients vs. donors. Naïve Th (p = 0.011) and CTL (p = 0.0007) were decreased, while activated Th (p = 0.0007) and CTL (p = 0.0003) were increased. IFN-γ production and degranulation activity in NK and CTL were normal. Peripheral cytokines showed an altered profile vs. donors, particularly elevated IL-6 (p = 0.008) and TGF-β (p = 0.041). Total hepatic CTLs favored damage. Treg could not prevent fibrogenesis triggered by Th17 and IL-8. Peripheral T-lymphocyte differentiation stage shift, elevated cytokine levels and NK-cell count decrease would contribute to global disease.
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Affiliation(s)
- Daniela Alejandra Rios
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | | | - María Soledad Caldirola
- Immunology Unit, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - María Isabel Gaillard
- Immunology Unit, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - Cecilia Giadans
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | | | - Elena Noemí De Matteo
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - María Victoria Preciado
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - Pamela Valva
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
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23
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Reig M, Cabibbo G. Antiviral therapy in the palliative setting of HCC (BCLC-B and -C). J Hepatol 2021; 74:1225-1233. [PMID: 33582128 DOI: 10.1016/j.jhep.2021.01.046] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 01/06/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
The potential impact of direct-acting antivirals (DAAs) in patients with Barcelona Clinic Liver Cancer (BCLC)-B/C stage hepatocellular carcinoma (HCC) is understudied. Patients with HCC have been systematically excluded from randomised controlled trials evaluating the effectiveness of DAAs. Thus, the benefits of DAAs in patients with HCC are less well defined. The presence of active HCC before the initiation of DAA treatment is reported to be a predictor of DAA failure, and studies in patients without HCC have demonstrated that improvements in cirrhosis complications were lower or absent after DAA failure. Even if viral eradication is achieved using DAAs, reversal of liver function impairment may take longer than the development of end-stage cancer status. Additionally, the impact of DAAs on HCC recurrence is still a controversial topic. Thus, the decision of whether to use DAAs should be made on a patient-by-patient basis, and each patient should be informed of all the potential risks and benefits associated with their usage. This document summarises the current data on the usage of DAAs in BCLC-B/C patients, discusses the concept of "the point of no return" in the setting of DAAs, and proposes tools for deciding the best option for each patient profile. If liver function improvement overlaps with symptomatic HCC progression, the benefits of DAAs could be minimised, worsened, or fully counterbalanced. If the BCLC stage is defined using only liver dysfunction, the decision to prioritise DAA treatment should be based on the option (or lack thereof) of liver transplantation and/or the HCC stage. We propose applying a shared decision-making approach, informing each patient of all the potential risks and benefits of the proposed medical intervention.
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Affiliation(s)
- Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, IMDiM, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
| | - Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
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24
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Lockart I, Hajarizadeh B, Alavi M, Davison S, Prakoso E, Levy MT, George J, Dore GJ, Danta M. Hepatitis C virus cure before hepatocellular carcinoma diagnosis is associated with improved survival. J Viral Hepat 2021; 28:710-718. [PMID: 33481322 DOI: 10.1111/jvh.13475] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023]
Abstract
The impact of hepatitis C virus (HCV) cure on survival in patients with HCV-related hepatocellular carcinoma (HCC) has been examined, although many studies have been subject to survivor treatment selection bias. We assessed the impact of HCV cure before HCC diagnosis on overall survival. Patients with HCV-related HCC at three referral hospitals in Australia were included retrospectively (January 2008 to December 2019). The risk of death following HCC diagnosis among patients who achieved HCV cure before HCC diagnosis was compared to patients who were viraemic at diagnosis. Among 422 patients with HCV-related HCC, 101 (24%) achieved HCV cure before HCC diagnosis, 37 with interferon (IFN) and 64 with direct-acting antiviral (DAA) therapy. Patients with HCV cure were more likely to have no cirrhosis or Child-Pugh A liver disease (83% vs. 66%, p = .002), surveillance detection (71% vs. 48%, p < .001), HCC stage O or A (64% vs. 45%, p < .001) and receive curative initial HCC management (51% vs. 28%, p < .001), compared with patients who were viraemic at diagnosis. The 5-year overall survival was 51% in the HCV cure group and 22% in the viraemic group. In adjusted analysis, risk of death was lower in patients with HCV cure before HCC diagnosis compared with patients who were viraemic at diagnosis (adjusted hazard ratio: 0.63; 95% CI: 0.44-0.91; p = .013). Patients with HCV-related HCC who have achieved HCV cure before HCC diagnosis have improved overall survival compared with patients who were viraemic at diagnosis.
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Affiliation(s)
- Ian Lockart
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.,St Vincent's Hospital, Sydney, NSW, Australia
| | | | - Maryam Alavi
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Scott Davison
- Liverpool Hospital, Sydney, NSW, Australia.,South Western Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Emilia Prakoso
- Liverpool Hospital, Sydney, NSW, Australia.,Central Clinical School, The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Miriam T Levy
- Liverpool Hospital, Sydney, NSW, Australia.,South Western Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Sydney, NSW, Australia
| | - Gregory J Dore
- St Vincent's Hospital, Sydney, NSW, Australia.,The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Mark Danta
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.,St Vincent's Hospital, Sydney, NSW, Australia
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25
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Kwan BS, Kim JH, Park SJ, Choe WH, Kwon SY, Yoo BC. Comparison of the efficacy and safety of direct-acting antiviral therapy with or without hepatitis C-related hepatocellular carcinoma. Korean J Intern Med 2021; 36:292-304. [PMID: 32241083 PMCID: PMC7969069 DOI: 10.3904/kjim.2019.297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/24/2019] [Accepted: 11/24/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND/AIMS Chronic hepatitis C (CHC) treatment has dramatically improved since direct-acting antiviral (DAA) therapy was introduced. However, the use of DAA therapy in CHC patients with hepatocellular carcinoma (HCC) remains controversial. We investigated the DAA treatment response in CHC patients with HCC. METHODS We retrospectively analyzed CHC patients treated with DAA from 2016 to 2018. Patients were divided into two groups based on their HCC-history before DAA therapy. Baseline characteristics, sustained virologic response at 12 weeks (SVR 12), and HCC recurrence after DAA therapy were evaluated. We also used propensity score matching (PSM) in a 2:1 ratio to reduce confounding variables. RESULTS A total of 192 patients were enrolled; 78.1% were treatment-naïve, and 34.9% had liver cirrhosis (LC). Among these patients, 168 did not have HCC, and 24 had HCC. The HCC group was older (57.0 years vs. 72.0 years, p < 0.001), had a higher incidence of LC (26.2% vs. 95.8%, p < 0.001), fibrosis-4 index (2.6 vs. 9.2, p < 0.001), liver stiffness measurement (7.0 kPa vs. 17.4 kPa, p = 0.012), and α-fetoprotein (4.4 ng/mL vs. 8.2 ng/mL, p ≤ 0.001). The SVR 12 rate was 97.0% in the non- HCC group and 91.7% in the HCC group (p = 0.213). HCC recurrence was observed in 14 patients (58.3%) in the HCC group. CONCLUSION DAA treatment efficacy in CHC patients with or those without HCC were not significantly different, and HCC recurrence was relatively common.
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Affiliation(s)
- Byung Soo Kwan
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
| | - Seong Jun Park
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Byung-Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
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26
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Kim D, Konyn P, Cholankeril G, Wong RJ, Younossi ZM, Ahmed A. Decline in Annual Mortality of Hepatitis C Virus-Related Hepatocellular Carcinoma in the United States, From 2009 to 2018. Gastroenterology 2020; 159:1558-1560.e2. [PMID: 32389664 DOI: 10.1053/j.gastro.2020.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/26/2020] [Accepted: 05/04/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.
| | - Peter Konyn
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Highland Hospital, Oakland, California
| | - Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia; Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
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27
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Direct Antiviral Treatments for Hepatitis C Virus Have Off-Target Effects of Oncologic Relevance in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12092674. [PMID: 32961688 PMCID: PMC7565876 DOI: 10.3390/cancers12092674] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Hepatitis C virus (HCV) eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma incidence in cirrhosis; however, contrasting evidence on higher incidence of hepatocellular carcinoma (HCC) was reported in patients previously treated for HCC. Here, we showed that sofosbuvir and daclatasvir can modulate cell proliferation, invasion capability and gene expression in HCC-derived cell lines, suggesting that off-target effects of these drugs might be responsible for both the increase and reduction of cell proliferation and migration capability. Off-target gene modulation, mainly affecting mitochondrial functions, ribosomal genes and histones, was consistent with matched phenotypic changes and might account either for pro-oncogenic or tumor-suppressive functions of DAAs, that seemed to be dictated by the molecular background. Abstract Background and Aims: HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; however, contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC. Methods: we investigated whether sofosbuvir and daclatasvir modulate cell proliferation, invasion capability and gene expression (RNA-seq) in HCC-derived cell lines, hypothesizing possible off-target effects of these drugs. Results observed in HCC cell lines were validated in non-HCC cancer-derived cell lines and a preliminary series of human HCC tissues by qPCR and IHC. Results: DAAs can affect HCC cell proliferation and migration capability by either increasing or reducing them, showing transcriptomic changes consistent with some unexpected drug-associated effects. Off-target gene modulation, mainly affecting ribosomal genes, mitochondrial functions and histones, points to epigenetics and proliferation as relevant events, consistent with matched phenotypic changes. A preliminary validation of in vitro findings was performed in a restricted cohort of HCC patients previously treated with DAAs, with immunohistochemical correlations suggesting DAA-treated HCCs to be more aggressive in terms of migration and epidermal-to-mesenchymal transition. Conclusions: Our findings suggested the possible occurrence of off-target effects ultimately modulating cell proliferation and/or migration and potentially justified previous findings showing some instances of particularly aggressive HCC recurrence as well as reduced incidence of recurrence of HCC following treatment with DAAs.
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28
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Sakai H, Miwa T, Ikoma Y, Hanai T, Nakamura N, Imai K, Kitagawa J, Shirakami Y, Kanemura N, Suetsugu A, Takai K, Shiraki M, Shimizu M. Development of diffuse large B-cell lymphoma after sofosbuvir-ledipasvir treatment for chronic hepatitis C: A case report and literature review. Mol Clin Oncol 2020; 13:1. [PMID: 32754315 PMCID: PMC7391802 DOI: 10.3892/mco.2020.2071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Recently, treatments for chronic hepatitis C virus (HCV) infection have significantly improved by the development of direct-acting antiviral agents (DAAs) and almost all patients with HCV can complete antiviral treatment without apparent adverse events. Malignant lymphoma, particularly B-cell non-Hodgkin's lymphoma, is one of the extrahepatic manifestations associated with chronic HCV infection. The effectiveness of anti-HCV therapy with DAAs for B-cell non-Hodgkin's lymphoma has been demonstrated in recent reports, whereas late-onset B-cell non-Hodgkin's lymphoma after HCV eradication with DAAs has occasionally been reported. In the present study, a 77-year-old man with chronic hepatitis C and intermediate liver cancer risk received sofosbuvir-ledipasvir treatment for 12 weeks. Two months following the end of antiviral therapy, he had achieved sustained virologic response for 8 weeks. However, the patient occasionally found swelling of the right cervical lymph nodes without any subjective symptoms. Lymph node biopsy revealed diffuse large B-cell lymphoma and whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography showed increased FDG uptake in the right cervical, right submandibular, mediastinal and mesenteric lymph nodes. The patient received six courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and achieved complete response at 8 months after chemotherapy initiation. Thus, the development of lymphoid malignancies may arise, even after HCV eradication with DAAs. Therefore, clinicians should be aware of such risks during and after antiviral treatment with DAAs.
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Affiliation(s)
- Hiroyasu Sakai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Takao Miwa
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yoshikazu Ikoma
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Nobuhiko Nakamura
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Kenji Imai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Junichi Kitagawa
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Nobuhiro Kanemura
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Koji Takai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Makoto Shiraki
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
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Peng Y, Wei Q, He Y, Xie Q, Liang Y, Zhang L, Xia Y, Li Y, Chen W, Zhao J, Chai J. ALBI versus child-pugh in predicting outcome of patients with HCC: A systematic review. Expert Rev Gastroenterol Hepatol 2020; 14:383-400. [PMID: 32240595 DOI: 10.1080/17474124.2020.1748010] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 03/24/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is an aggressive tumor type which results in poor prognosis. ALBI and Child-Pugh score have been widely applied for predicting prognosis in patients with liver diseases. We conducted a systematic review to compare the prognostic ability of ALBI versus Child-Pugh in HCC patients. AREAS COVERED PubMed, EMBASE and Cochrane Library were explored. The data were extracted from every study. Studies investigating HCC patients and comparing the predicting ability between ALBI and Child-Pugh were analyzed. EXPERT OPINION This systematic review revealed that ALBI showed better discriminative ability than Child-Pugh for predicting the prognosis in HCC patients. However, the predictive abilities of two scores should be improved. Except for the most common used serum biomarker AFP for diagnosis and surveillance of HCC, recent studies have also explored all aspects of HCC through genome-wide sequencing, exome sequencing, RNA sequencing and genome-wide methylation analysis which provide essential clues for genotyping of HCC. Further studies should explore biomarkers by advanced techniques to validate new prognostic tools for early diagnosis and prognosis of HCC. Moreover, multicenter prospective studies should be carried out to compare the prognostic values of predictive indicators in HCC population in the future.
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Affiliation(s)
- Ying Peng
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Qinglin Wei
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Yonghong He
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Qiaoling Xie
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Yanchao Liang
- Pulmonary and Critical Care Medicine 1, The Affiliated Zhuzhou Hospital Xiangya Medical College CSU , Zhuzhou City, Hunan Province, China
| | - Liangjun Zhang
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Yiju Xia
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Yan Li
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Wensheng Chen
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Jingjing Zhao
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
| | - Jin Chai
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University) , Chongqing, China
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Network Pharmacology-Based Strategy for Predicting Therapy Targets of Traditional Chinese Medicine Xihuang Pill on Liver Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:6076572. [PMID: 32256653 PMCID: PMC7102465 DOI: 10.1155/2020/6076572] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 01/16/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023]
Abstract
Objective To investigate the potential therapy targets and pharmacological mechanism of traditional Chinese medicine (TCM) Xihuang pill in liver cancer based on network pharmacology. Methods Drug ingredients-target network was constructed based on the target sets of Xihuang pill and liver cancer. The overlapping genes between Xihuang pill targets and liver cancer-related molecular targets were investigated using comparative analysis. Moreover, the PPI network and module was constructed based on overlapping genes and hub nodes, respectively, followed by the pathway enrichment analysis. Results A drug ingredients-target network was established with 1184 nodes and 11035 interactions. Moreover, a total of 106 overlapping genes were revealed between drug targets and liver cancer molecular targets. Furthermore, a PPI network and 4 modules were further investigated based on overlapping genes, respectively. These hub nodes such as VEGFA and EGFR were mainly enriched in GO functions including positive regulation of MAP kinase activity, activation of protein kinase activity, regulation of MAP kinase activity, and pathways like proteoglycans in cancer, bladder cancer, and estrogen signaling. Conclusion VEGFA and EGFR might be potential therapy targets of Xihuang pill in liver cancer. Furthermore, the effect of Xihuang pill on liver cancer might be realized by targeting VEGFA and EGFR in pathways like proteoglycans in cancer and estrogen signaling.
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Wen Q, Han T, Wang Z, Jiang S. Role and mechanism of programmed death-ligand 1 in hypoxia-induced liver cancer immune escape. Oncol Lett 2020; 19:2595-2601. [PMID: 32218809 PMCID: PMC7068669 DOI: 10.3892/ol.2020.11369] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 10/10/2019] [Indexed: 12/24/2022] Open
Abstract
Immune escape plays a vital role in the development of liver cancer. The interaction between programmed death-ligand 1 (PD-L1) and programmed cell death-1 is a key mediator of cancer immune escape, which leads to the suppression of anticancer immunity and promotion of tumor progression. Hypoxia is a common phenomenon in the tumor microenvironment. Under hypoxic conditions, suppressive immune cells, such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, are frequently recruited to tumor tissues to form the immunosuppressive microenvironment in liver cancer. These cells secrete cancer-promoting inflammatory cytokines, which activate the STAT3 and NF-κB signaling pathways. Recent studies have shown that STAT3 is associated with NF-κB and that these transcription factors are often co-activated to regulate tumor proliferation, survival, angiogenesis and invasion. The activation of STAT3 and NF-κB signaling pathways can directly and indirectly induce PD-L1 expression. Therefore, further understanding of the association between hypoxia and PD-L1 may help in the future treatment of liver cancer. The present review summarizes the recent progresses on PD-L1-mediated regulation and facilitation of liver cancer cell immune escape in response to hypoxia.
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Affiliation(s)
- Qingxian Wen
- Clinical Medical Laboratory Center, Jining No. 1 People's Hospital, Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Tao Han
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Zijian Wang
- Department of Radiation Oncology, Shandong Cancer Hospital, Shandong First Medical University, Jinan, Shandong 250000, P.R. China
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining No. 1 People's Hospital, Jining Medical University, Jining, Shandong 272000, P.R. China
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He S, Lockart I, Alavi M, Danta M, Hajarizadeh B, Dore GJ. Systematic review with meta-analysis: effectiveness of direct-acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma. Aliment Pharmacol Ther 2020; 51:34-52. [PMID: 31808566 DOI: 10.1111/apt.15598] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/25/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection is highly curative and tolerable. Among patients with hepatocellular carcinoma (HCC), optimal timing of DAA therapy remains unclear. Data on efficacy of DAA therapy in patients with HCC would inform this decision-making. AIM To evaluate response to DAA therapy among patients diagnosed with HCV infection and HCC. METHODS Bibliographic databases and conference abstracts were searched. Meta-analysis was conducted to pool sustained virologic response (SVR) estimates. RESULTS Fifty-six studies with 5522 patients with HCV and HCC were included. Overall SVR was 88.3% (95% CI 86.1-90.4). Twenty-seven studies included patients with prior or present HCC (n = 3126) and patients without HCC (n = 49 138), in which SVR was 88.2% (95% CI 85.0-91.4) and 92.4% (95% CI 91.1-93.7) among patients with and without HCC, respectively (odds ratio: 0.54, 95% CI 0.43-0.68, P < .001). In the subgroup analyses, higher SVR was seen in patients who received curative HCC management (SVR 90.4%, 95% CI 88.3-92.4), or treated with sofosbuvir + NS5A inhibitor DAAs (SVR 96.9%, 95% CI 94.3-99.4), or in patients with HCV genotype 1 infection (SVR 92.0%, 95% CI 88.1-95.6). CONCLUSION Response to DAA therapy was lower in patients with HCC compared to those without HCC, regardless of cirrhosis status. Among HCC patients, there was an impact of proportion with curative HCC management on DAA therapy response.
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Affiliation(s)
- Sichan He
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Ian Lockart
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.,St Vincent's Hospital, Sydney, NSW, Australia
| | - Maryam Alavi
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Mark Danta
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.,St Vincent's Hospital, Sydney, NSW, Australia
| | | | - Gregory J Dore
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.,St Vincent's Hospital, Sydney, NSW, Australia
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Antwi SO, Van Houten HK, Sangaralingham LR, Patel T. Risk of De Novo Hepatocellular Carcinoma Following Use of Direct Acting Antiviral Medications for Treatment of Chronic Hepatitis C. Cancer Prev Res (Phila) 2019; 12:891-902. [PMID: 31451519 PMCID: PMC6893130 DOI: 10.1158/1940-6207.capr-19-0162] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/17/2019] [Accepted: 08/19/2019] [Indexed: 12/17/2022]
Abstract
Direct-acting antivirals (DAA) are now the mainstay of treatment for patients with chronic hepatitis C virus (HCV); however, there is some controversy over whether use of DAAs for HCV, as compared with IFN-based regimens, leads to an increased risk for hepatocellular carcinoma (HCC) development. We investigated the association between use of DAAs and subsequent development of HCC in longitudinal data from patients with HCV from diverse backgrounds (various ages, ethnicities, and geographic regions) across the United States. The design was a retrospective study performed using medical and pharmacy claims from OptumLabs. HCV treatment exposure was categorized as DAA-only, DAA + IFN, any-DAA, or IFN-only. To account for confounding by indication, inverse probability of treatment weighting was performed. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). We identified 5,781 patients with HCV with no history of HCC at baseline. Compared with IFN-only regimen, no significant increase in HCC risk was found for use of DAA-only (HR, 1.53; 95% CI, 0.73-3.23), DAA + IFN (HR, 1.02; 95% CI, 0.51-2.06), or any-DAA (HR, 1.04; 95% CI, 0.65-1.65). When stratified by sustained virological response (SVR), we noted a higher HCC risk for DAA-only among patients who achieved SVR post-treatment (HR, 7.53; 95% CI, 1.48-38.34), but the CIs were wide, which might be due to the small sample size of the subgroups. Among those who did not achieve SVR, no association was found for use of DAA-only (HR, 0.59; 95% CI, 0.19-1.91). These findings do not provide compelling evidence for the conception that use of DAAs for HCV is associated with increased risk of HCC development.
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Affiliation(s)
- Samuel O Antwi
- Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida.
| | - Holly K Van Houten
- Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
- OptumLabs, Cambridge, Massachusetts
| | - Lindsey R Sangaralingham
- Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota
- OptumLabs, Cambridge, Massachusetts
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida.
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El Kassas M, Tawheed A, Eltabbakh M, Kaseb A. Hepatitis C Antiviral Therapy In Patients With Successfully Treated Hepatocellular Carcinoma: Dancing With Wolves. J Hepatocell Carcinoma 2019; 6:183-191. [PMID: 31819865 PMCID: PMC6879003 DOI: 10.2147/jhc.s206668] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 10/21/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) infection is known to be one of the leading causes of hepatocellular carcinoma (HCC) all over the world. Previously, multiple studies have confirmed a decreased rate of HCC occurrence or recurrence in the cases of hepatitis C associated cirrhosis after treatment with interferon, in comparison to the untreated cases, even in the absence of clearance of HCV. Treatment programs with direct-acting antivirals (DAAs) as a new method for HCV treatment and cure in 2014, with higher safety and efficacy, were considered as an important step in the treatment of patients with history of HCC, improving their overall prognosis. Recently, reports coming from various European centers claimed that the risk of HCC increased following DAAs therapy, especially in cases with previous HCC. Moreover, other studies revealed that the recurrence of HCC after DAAs treatment was more aggressive. Even though others were not able to conclude the same results, the role of DAA therapy in recurrence of HCC in patients with previous HCC after sustained virological response (SVR) achievement remains questionable. This review explored the existing literature and discussed opinions on the possibility of increasing recurrence of HCC following DAA therapy, possible mechanisms, predictors of HCC recurrence post DAAs, and whether those patients should be treated or not.
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Affiliation(s)
- Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Ahmed Tawheed
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Mohamed Eltabbakh
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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Singal AG, Rich NE, Mehta N, Branch AD, Pillai A, Hoteit M, Volk M, Odewole M, Scaglione S, Guy J, Said A, Feld JJ, John BV, Frenette C, Mantry P, Rangnekar AS, Oloruntoba O, Leise M, Jou JH, Bhamidimarri KR, Kulik L, Ioannou GN, Huang A, Tran T, Samant H, Dhanasekaran R, Duarte-Rojo A, Salgia R, Eswaran S, Jalal P, Flores A, Satapathy SK, Kagan S, Gopal P, Wong R, Parikh ND, Murphy CC. Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma. Gastroenterology 2019; 157:1253-1263.e2. [PMID: 31374215 PMCID: PMC6815711 DOI: 10.1053/j.gastro.2019.07.040] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 06/24/2019] [Accepted: 07/22/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. METHODS We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 health care systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting. RESULTS Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18-0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55-2.33). CONCLUSIONS In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas.
| | - Nicole E Rich
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
| | - Neil Mehta
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - Andrea D Branch
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
| | - Maarouf Hoteit
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael Volk
- Transplantation Institute and Division of Gastroenterology, Loma Linda University Health, Loma Linda, California
| | - Mobolaji Odewole
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
| | - Steven Scaglione
- Division of Hepatology, Loyola University Medical Center and Edward Hines Veterans Affairs, Hines, Illinois
| | - Jennifer Guy
- Department of Transplantation, California Pacific Medical Center, San Francisco, California
| | - Adnan Said
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine, Madison, Wisconsin
| | - Jordan J Feld
- Toronto Center for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Binu V John
- Division of Gastroenterology and Hepatology, McGuire VA Medical Center, Richmond, Virginia
| | - Catherine Frenette
- Division of Organ Transplantation, Scripps Green Hospital, San Diego, California
| | | | - Amol S Rangnekar
- Division of Gastroenterology, Georgetown University Hospital, Washington, District of Columbia
| | - Omobonike Oloruntoba
- Division of Gastroenterology and Hepatology, Duke University Health Center, Durham, North Carolina
| | - Michael Leise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Janice H Jou
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon
| | | | - Laura Kulik
- Division of Hepatology, Northwestern University, Chicago, Illinois
| | - George N Ioannou
- Division of Gastroenterology and Research and Development, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington
| | - Annsa Huang
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - Tram Tran
- Liver Disease and Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Hrishikesh Samant
- Division of Gastroenterology and Hepatology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | | | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Reena Salgia
- Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan
| | - Sheila Eswaran
- Division of Gastroenterology, Rush Medical College, Chicago, Illinois
| | - Prasun Jalal
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas
| | - Avegail Flores
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
| | - Sanjaya K Satapathy
- Division of Hepatology, Donald and Barbara Zucker School of Medicine, Northshore University Hospital, Northwell Health, Manhasset, New York
| | - Sofia Kagan
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
| | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas
| | - Robert Wong
- Division of Gastroenterology and Hepatology, Alameda Health System, Oakland, California
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | - Caitlin C Murphy
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
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Hernáez-Alsina T, Caballol-Oliva B, Díaz-González Á, Guedes-Leal C, Reig M. Risk of recurrence of hepatocellular carcinoma in patients treated with interferon-free antivirals. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:502-511. [PMID: 31472990 DOI: 10.1016/j.gastrohep.2019.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 05/01/2019] [Accepted: 05/07/2019] [Indexed: 12/18/2022]
Abstract
Eradication of the hepatitis C virus (HCV) with interferon-free therapies (DAAs) has modified the course of the disease, as the rate of patients with compensated cirrhosis who achieve a sustained virological response exceeds 95%. However, the impact on development of hepatocellular carcinoma (HCC) is currently in dispute. This argument could be divided into different key points: the impact of DAA on rate of HCC recurrence, the temporal link between starting DAAs and HCC recurrence, and finally, the aggressive pattern of HCC. Therefore, the aim of this review is to analyse the available results in this population of patients from a clinical perspective where the risks and benefits of HCV eradication with DAA therapies are evaluated in patients with complete response of HCC.
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Affiliation(s)
- Tania Hernáez-Alsina
- Servicio de Aparato Digestivo, Hospital San Pedro, Logroño, La Rioja, España; Grupo BCLC, Unidad de Oncología Hepática, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, España
| | - Berta Caballol-Oliva
- Grupo BCLC, Unidad de Oncología Hepática, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, España
| | - Álvaro Díaz-González
- Grupo BCLC, Unidad de Oncología Hepática, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, España
| | - Cassia Guedes-Leal
- Grupo BCLC, Unidad de Oncología Hepática, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, España
| | - María Reig
- Grupo BCLC, Unidad de Oncología Hepática, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universidad de Barcelona, Barcelona, España.
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Hepatocellular metastasis recurrence in liver transplant after treatment with direct antiviral agents. Clin J Gastroenterol 2019; 13:260-266. [PMID: 31410743 DOI: 10.1007/s12328-019-01031-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 08/06/2019] [Indexed: 10/26/2022]
Abstract
Chronic HCV liver infection is considered one of the main causes of liver cirrhosis and hepatocellular carcinoma (HCC). For a selected group of patients, orthotopic liver transplantation (OLTx) is the most effective option to cure both liver diseases. After liver transplantation, patients may be at risk of viral infection reactivation and HCC recurrence. HCV recurrence on the transplanted organ can lead to graft cirrhosis and therefore the clearance of virus with antiviral therapies has a pivotal role on the prevention of graft damage. Nowadays, direct antiviral agents (DAAs) represent the choice treatment for HCV recurrence in liver transplanted patients, ensuring high eradication rates. We present the case of a liver transplant recipient who developed, 7 years after OLTx and immediately after a DAAs treatment, a subcutaneous abdominal mass with histological characteristics of HCC.
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Piñero F, Mendizabal M, Ridruejo E, Herz Wolff F, Ameigeiras B, Anders M, Schinoni MI, Reggiardo V, Palazzo A, Videla M, Alonso C, Santos L, Varón A, Figueroa S, Vistarini C, Adrover R, Fernández N, Perez D, Tanno F, Hernández N, Sixto M, Borzi S, Bruno A, Cocozzella D, Soza A, Descalzi V, Estepo C, Zerega A, de Araujo A, Cheinquer H, Silva M. Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma. Liver Int 2019; 39:1033-1043. [PMID: 30636361 DOI: 10.1111/liv.14041] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/14/2018] [Accepted: 12/30/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Data from Europe and North America have been published regarding the risk of developing hepatocellular carcinoma (HCC) after treatment with direct antiviral agents (DAA). We proposed to evaluate cumulative incidence and associated risk factors for de novo HCC. METHODS This was a prospective multicentre cohort study from Latin America including 1400 F1-F4-treated patients with DAAs (F3-F4 n = 1017). Cox proportional regression models (hazard ratios, HR and 95% CI) were used to evaluate independent associated variables with HCC. Further adjustment with competing risk regression and propensity score matching was carried out. RESULTS During a median follow-up of 16 months (IQR 8.9-23.4 months) since DAAs initiation, overall cumulative incidence of HCC was 0.02 (CI 0.01; 0.03) at 12 months and 0.04 (CI 0.03; 0.06) at 24 months. Cumulative incidence of HCC in cirrhotic patients (n = 784) was 0.03 (CI 0.02-0.05) at 12 months and 0.06 (CI 0.04-0.08) at 24 months of follow-up. Failure to achieve SVR was independently associated with de novo HCC with a HR of 4.9 (CI 1.44; 17.32), after adjusting for diabetes mellitus, previous interferon non-responder, Child-Pugh and clinically significant portal hypertension. SVR presented an overall relative risk reduction for de novo HCC of 73% (CI 15%-91%), 17 patients were needed to be treated to prevent one case of de novo HCC in this cohort. CONCLUSIONS Achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remained high in patients with advanced fibrosis, thus demanding continuous surveillance strategies in this population.
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Affiliation(s)
| | | | - Ezequiel Ridruejo
- Hospital Universitario Austral, Pilar, Argentina
- Centro de Educación Médica e Investigaciones Clínicas, Buenos Aires, Argentina
| | | | | | | | | | | | - Ana Palazzo
- Hospital Padilla, San Miguel de Tucumán, Argentina
| | - María Videla
- Sanatorio Sagrado Corazón, Buenos Aires, Argentina
| | | | | | | | | | | | | | | | | | | | | | | | | | - Andres Bruno
- Hospital Cosme Argerich, Buenos Aires, Argentina
| | | | - Alejandro Soza
- Hospital Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | | | | | | | - Hugo Cheinquer
- Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Singal AG, Lim JK, Kanwal F. AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review. Gastroenterology 2019; 156:2149-2157. [PMID: 30878469 PMCID: PMC6529246 DOI: 10.1053/j.gastro.2019.02.046] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 02/19/2019] [Indexed: 02/08/2023]
Abstract
DESCRIPTION The purpose of this clinical practice update is to evaluate the evidence describing the interaction between direct-acting antiviral (DAA) therapy for hepatitis and hepatocellular carcinoma (HCC) with regard to HCC incidence, HCC recurrence, and DAA efficacy, and to summarize best practice advice regarding HCC surveillance and timing of DAA therapy. METHODS The recommendations outlined in this expert review are based on available published evidence, including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis. BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment. BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance. BEST PRACTICE ADVICE 4: HCC surveillance should be performed using ultrasound with or without α-fetoprotein every 6 months. Current data do not support shorter surveillance intervals or the use of alternative surveillance modalities. BEST PRACTICE ADVICE 5: Future studies may show a reduction in HCC risk over time after DAA-induced sustained virologic response. However, in the interim, HCC surveillance should continue indefinitely if patients are otherwise eligible for potentially curative therapy. BEST PRACTICE ADVICE 6: The presence of active HCC is associated with a small but statistically significant decrease in sustained virologic response with DAA therapy. BEST PRACTICE ADVICE 7: Patients with HCC who are eligible for potentially curative therapy with liver resection or ablation should defer DAA therapy until after HCC treatment is completed. BEST PRACTICE ADVICE 8: Timing of DAA therapy for patients with HCC who are listed for liver transplantation should be determined with consideration of median wait times, availability of hepatitis C virus-positive organs, and degree of liver dysfunction. BEST PRACTICE ADVICE 9: There are insufficient data evaluating benefits and cost-effectiveness of DAA therapy in patients with active intermediate or advanced HCC. Decisions regarding DAA treatment in these patients should be considered in light of HCC tumor burden, degree of liver dysfunction, life expectancy, and patient preferences. BEST PRACTICE ADVICE 10: There are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy. BEST PRACTICE ADVICE 11: DAA therapy should not be withheld from patients with complete response to HCC therapy; however, DAA therapy can be deferred 4-6 months to confirm response to HCC therapy. BEST PRACTICE ADVICE 12: Patients with complete response to HCC therapy who are treated with DAAs have a continued risk of HCC recurrence and require HCC surveillance, which should be conducted indefinitely with dynamic contrast-enhanced computed tomography or magnetic resonance imaging every 3-6 months. Current data do not support more frequent surveillance in these patients. This Clinical Practice Update was produced by the AGA Institute.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas.
| | - Joseph K Lim
- Yale Liver Center and Section of Digestive Diseases; Yale University School of Medicine, New Haven, Connecticut
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Houston Veterans Affairs Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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Singal AG, Rich NE, Mehta N, Branch A, Pillai A, Hoteit M, Volk M, Odewole M, Scaglione S, Guy J, Said A, Feld JJ, John BV, Frenette C, Mantry P, Rangnekar AS, Oloruntoba O, Leise M, Jou JH, Bhamidimarri KR, Kulik L, Tran T, Samant H, Dhanasekaran R, Duarte-Rojo A, Salgia R, Eswaran S, Jalal P, Flores A, Satapathy SK, Wong R, Huang A, Misra S, Schwartz M, Mitrani R, Nakka S, Noureddine W, Ho C, Konjeti VR, Dao A, Nelson K, Delarosa K, Rahim U, Mavuram M, Xie JJ, Murphy CC, Parikh ND. Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. Gastroenterology 2019; 156:1683-1692.e1. [PMID: 30660729 PMCID: PMC6598433 DOI: 10.1053/j.gastro.2019.01.027] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/15/2018] [Accepted: 01/09/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas.
| | - Nicole E Rich
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
| | - Neil Mehta
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - Andrea Branch
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
| | - Maarouf Hoteit
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael Volk
- Transplantation Institute and Division of Gastroenterology, Loma Linda University Health, Loma Linda, California
| | - Mobolaji Odewole
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
| | - Steven Scaglione
- Division of Hepatology, Loyola University Medical Center, Chicago, Illinois; Edward Hines Veterans Affairs, Chicago, Illinois
| | - Jennifer Guy
- Department of Transplantation, California Pacific Medical Center, San Francisco, California
| | - Adnan Said
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine, Madison, Wisconsin
| | - Jordan J Feld
- Toronto Center for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Binu V John
- Division of Gastroenterology and Hepatology, McGuire VA Medical Center, Richmond, Virginia
| | - Catherine Frenette
- Division of Organ Transplantation, Scripps Green Hospital, San Diego, California
| | | | - Amol S Rangnekar
- Division of Gastroenterology, Georgetown University Hospital, Washington, DC
| | - Omobonike Oloruntoba
- Division of Gastroenterology and Hepatology, Duke University Health Center, Durham, North Carolina
| | - Michael Leise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Janice H Jou
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon
| | | | - Laura Kulik
- Division of Hepatology, Northwestern University, Chicago, Illinois
| | - Tram Tran
- Liver Disease and Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Hrishikesh Samant
- Division of Gastroenterology and Hepatology, Louisiana State University Health Sciences Center, Baton Rouge, Louisiana
| | | | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Reena Salgia
- Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan
| | - Sheila Eswaran
- Division of Gastroenterology, Rush Medical College, Chicago, Illinois
| | - Prasun Jalal
- Division of Abdominal Transplantation, Baylor College of Medicine, Dallas, Texas
| | - Avegail Flores
- Division of Gastroenterology, Washington University School of Medicine, Louis, Missouri
| | - Sanjaya K Satapathy
- Division of Transplant Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Robert Wong
- Division of Gastroenterology and Hepatology, Alameda Health System, Oakland, California
| | - Annsa Huang
- Division of Gastroenterology, University of California San Francisco, San Francisco, California
| | - Suresh Misra
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Myron Schwartz
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Robert Mitrani
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sasank Nakka
- Transplantation Institute and Division of Gastroenterology, Loma Linda University Health, Loma Linda, California
| | - Wassim Noureddine
- Transplantation Institute and Division of Gastroenterology, Loma Linda University Health, Loma Linda, California
| | - Chanda Ho
- Department of Transplantation, California Pacific Medical Center, San Francisco, California
| | - Venkata R Konjeti
- Division of Gastroenterology and Hepatology, McGuire VA Medical Center, Richmond, Virginia
| | - Alexander Dao
- Division of Gastroenterology, Georgetown University Hospital, Washington, DC
| | - Kevin Nelson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Kelly Delarosa
- Liver Disease and Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Usman Rahim
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, California
| | - Meher Mavuram
- Division of Gastroenterology and Hepatology, Louisiana State University Health Sciences Center, Baton Rouge, Louisiana
| | - Jesse J Xie
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Caitlin C Murphy
- Division of Digestive and Liver Disease, UT Southwestern Medical Center, Dallas, Texas
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
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Sanduzzi-Zamparelli M, Boix L, Leal C, Reig M. Hepatocellular Carcinoma Recurrence in HCV Patients Treated with Direct Antiviral Agents. Viruses 2019; 11:E406. [PMID: 31052463 PMCID: PMC6563506 DOI: 10.3390/v11050406] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/23/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023] Open
Abstract
The risk of hepatocellular carcinoma recurrence is universal regardless of the treatment modality applied, and secondary prevention is still an unmet issue even though the elimination of hepatitis C (HCV) with direct antiviral agents (DAAs) was expected to be one of the new options. Unfortunately, the impact of DAAs on hepatocellular carcinoma (HCC) development (de novo and recurrence) is still controversial. Since the first publication on the subject in 2016, almost all groups worldwide have carried out research in this field with hundreds of publications now available. This revision is focused on the impact of DAAs on HCC recurrence and aims to discuss the potential underlying mechanisms and host factors pointing out the time association phenomenon between DAA treatment and HCC recurrence. Moreover, we comment on the methodological issues that could affect the different interpretations of the published results. In conclusion, this is an area of research with potential in the understanding of the impact of factors not previously considered, and may also help change hepatocarcinogenesis tenets, such as the belief that the elimination of HCV should be used as a second prevention treatment.
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Affiliation(s)
- Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - Loreto Boix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
- Centro de Investigación Médica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Cassia Leal
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - María Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
- Centro de Investigación Médica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.
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Hazari MAH. Failing immune surveillance in humans: Repercussion of modern day lifestyles. ANNALS OF MEDICAL PHYSIOLOGY 2019; 3:1-2. [DOI: 10.23921/amp.2019v3i1.38529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
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Lledó G, Benítez-Gutiérrez L, Arias A, Requena S, Cuervas-Mons V, de Mendoza C. Benefits of hepatitis C cure with antivirals: why test and treat? Future Microbiol 2019; 14:425-435. [PMID: 30900911 DOI: 10.2217/fmb-2019-0041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is one of the major causes of death worldwide due to infectious agents. The advent of direct-acting antivirals has dramatically improved the chance of HCV elimination, even for patients with decompensated cirrhosis. Along with HCV cure, benefits are recognized in terms of regression of liver fibrosis and risk of hepatocellular carcinoma. Furthermore, beyond hepatic outcomes, several extrahepatic benefits may result from sustained HCV eradication, including improvements in the neurocognitive function and reduced cardiovascular disease risk. Finally, there is no doubt that the individual success of direct-acting antivirals is largely contributing to halt HCV transmission globally, in the absence of an effective HCV prophylactic vaccine.
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Affiliation(s)
- Gema Lledó
- Internal Medicine Department, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
| | | | - Ana Arias
- Internal Medicine Department, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Silvia Requena
- Internal Medicine Department, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.,Internal Medicine Laboratory, Research Institute Puerta de Hierro-Segovia de Arana, Madrid, Spain
| | - Valentín Cuervas-Mons
- Internal Medicine Department, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.,Internal Medicine Laboratory, Research Institute Puerta de Hierro-Segovia de Arana, Madrid, Spain.,Universidad Autónoma, Madrid. Spain
| | - Carmen de Mendoza
- Internal Medicine Department, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.,Internal Medicine Laboratory, Research Institute Puerta de Hierro-Segovia de Arana, Madrid, Spain.,San Pablo-CEU University, Madrid. Spain
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Li Y, Wu Q, Yu G, Li L, Zhao X, Huang X, Mei W. Polypyridyl Ruthenium(II) complex-induced mitochondrial membrane potential dissipation activates DNA damage-mediated apoptosis to inhibit liver cancer. Eur J Med Chem 2019; 164:282-291. [DOI: 10.1016/j.ejmech.2018.12.041] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/11/2018] [Accepted: 12/17/2018] [Indexed: 12/25/2022]
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Owusu Sekyere S, Schlevogt B, Mettke F, Kabbani M, Deterding K, Wirth TC, Vogel A, Manns MP, Falk CS, Cornberg M, Wedemeyer H. HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection. Liver Cancer 2019; 8:41-65. [PMID: 30815394 PMCID: PMC6388568 DOI: 10.1159/000490360] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 05/19/2018] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis. DESIGN PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology. RESULTS Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epi-topes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs - with evidence of IL-12 being a major culprit. CONCLUSION Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.
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Affiliation(s)
- Solomon Owusu Sekyere
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bernhard Schlevogt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Friederike Mettke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Mohammad Kabbani
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Christian Wirth
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TTU-IICH, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover-Braunschweig, Germany,Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hanover, Germany
| | - Christine Susanne Falk
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,Institute of Transplantation Immunology (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TTU-IICH, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover-Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TTU-IICH, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover-Braunschweig, Germany,Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hanover, Germany,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany,*Prof. Dr. med. Heiner Wedemeyer, Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Hufelandstrasse 55, DE–45147 Essen (Germany), E-Mail
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Abstract
Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a "premetastasis niche" in the liver.
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Affiliation(s)
- Yoon Mee Yang
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - So Yeon Kim
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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Mun EJ, Green P, Berry K, Ioannou GN. No difference between direct-acting antivirals for hepatitis C in hepatocellular carcinoma risk. Eur J Gastroenterol Hepatol 2019; 31:47-52. [PMID: 30142097 PMCID: PMC6279503 DOI: 10.1097/meg.0000000000001242] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS It is unclear whether there are differences between direct-acting antivirals (DAAs) for hepatitis C virus in risk of hepatocellular carcinoma (HCC) after antiviral therapy. We aimed to compare different DAA regimens with respect to risk of de novo HCC following antiviral therapy. PATIENTS AND METHODS We identified 33 137 patients who initiated hepatitis C virus antiviral treatment in the Veterans Affair healthcare system between 6 December 2013 and 31 December 2015 with one of four DAA-only regimens (± ribavirin): paritaprevir/ritonavir/ombitasvir/dasabuvir (n=6289), sofosbuvir (n=4356), sofosbuvir+simeprevir (n=3210), and ledipasvir/sofosbuvir (n=19 282). We retrospectively followed patients until 15 June 2017 to identify incident (de novo) cases of HCC. We used propensity score-adjusted Cox proportional hazards regression to compare different DAA regimens with respect to HCC risk. RESULTS During a mean follow-up of 1.52 years, 741 new cases of HCC were diagnosed after antiviral treatment (annual incidence=1.47%). Patients treated with sofosbuvir+simeprevir had the highest annual HCC incidence (2.47%), followed by sofosbuvir (1.91%), ledipasvir/sofosbuvir (1.26%), and paritaprevir/ritonavir/ombitasvir/dasabuvir (0.95%). However, there were great differences between DAA-treated patients in the prevalence of cirrhosis, markers of advanced fibrosis, thrombocytopenia, and other HCC risk factors. After adjustment for baseline characteristics associated with HCC, there were no significant differences in HCC risk between the four DAA regimens. CONCLUSION There are no significant differences between DAA regimens in HCC risk after antiviral treatment. This suggests that DAAs do not have direct carcinogenic effects as it would be unlikely that different DAAs would have identical carcinogenic effects.
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Affiliation(s)
- Elijah J Mun
- Department of Internal Medicine, University of Washington
| | - Pamela Green
- Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, Washington, USA
| | - Kristin Berry
- Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, Washington, USA
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Healthcare System and University of Washington
- Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, Washington, USA
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Ioannou GN, Feld JJ. What Are the Benefits of a Sustained Virologic Response to Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection? Gastroenterology 2019; 156:446-460.e2. [PMID: 30367836 DOI: 10.1053/j.gastro.2018.10.033] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 09/26/2018] [Accepted: 10/03/2018] [Indexed: 02/06/2023]
Abstract
Direct-acting antiviral (DAA) regimens are safe and effective at eradicating hepatitis C virus (HCV) infection. Unfortunately, DAAs remain expensive, so treatment of all HCV-infected patients would substantially affect health care costs. It is therefore important to continue to assess the hepatic and extrahepatic benefits of a DAA-induced sustained virologic response (SVR). A DAA-induced SVR reduces a patient's risk of cirrhosis and hepatocellular carcinoma and extrahepatic manifestations of HCV infection; there are also data to indicate that an SVR can reduce mortality. SVR is a relevant clinical end point, but further analyses are required to confirm its importance among diverse HCV-infected populations and to document the public health benefits of HCV elimination at the population level. We review the evidence for the benefits associated with SVRs in different clinical settings and challenges to data collection.
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Affiliation(s)
- George N Ioannou
- Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington; Department of Medicine, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington; Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, Washington.
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada
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Cabibbo G, Celsa C, Cammà C, Craxì A. Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer? Liver Int 2018; 38:2108-2116. [PMID: 29935096 DOI: 10.1111/liv.13918] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 06/19/2018] [Indexed: 12/11/2022]
Abstract
Direct acting antivirals stabilize or improve liver function in the majority of patients with hepatitis C virus cirrhosis. Hepatic decompensation is the main driver of death of patients with early, successfully treated hepatocellular carcinoma superimposed to cirrhosis. Treatment with direct acting antivirals could improve the prognosis of these subjects, independently from the subsequent course of hepatocellular carcinoma, if the efficacy in obtaining viral clearance is as high as in patients without a history of hepatocellular carcinoma, and if the risk of hepatocellular carcinoma recurrence is unaffected. When dealing with hepatocellular carcinoma patients, direct acting antivirals can be indicated in two different settings: (a) subjects in which hepatocellular carcinoma has been already successfully treated ("cured" hepatocellular carcinoma), or (b) subjects whose hepatocellular carcinoma is still untreated or untreatable ("active" hepatocellular carcinoma). Although there are abundant data on "cured" hepatocellular carcinoma, evidence supporting treatment decisions in patients with "active" hepatocellular carcinoma is at best scarce and controversial, since these patients as well as patients with hepatocellular carcinoma listed for liver transplantation are usually excluded from treatment.
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Affiliation(s)
- Giuseppe Cabibbo
- Section of Gastroenterology, DIBIMIS, University of Palermo, Palermo, Italy
| | - Ciro Celsa
- Section of Gastroenterology, DIBIMIS, University of Palermo, Palermo, Italy
| | - Calogero Cammà
- Section of Gastroenterology, DIBIMIS, University of Palermo, Palermo, Italy
| | - Antonio Craxì
- Section of Gastroenterology, DIBIMIS, University of Palermo, Palermo, Italy
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Ferrarese A, Germani G, Gambato M, Russo FP, Senzolo M, Zanetto A, Shalaby S, Cillo U, Zanus G, Angeli P, Burra P. Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study. World J Gastroenterol 2018; 24:4403-4411. [PMID: 30344424 PMCID: PMC6189844 DOI: 10.3748/wjg.v24.i38.4403] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 07/26/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate waiting list (WL) registration and liver transplantation (LT) rates in patients with hepatitis C virus (HCV)-related cirrhosis since the introduction of direct-acting antivirals (DAAs). METHODS All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectively-updated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/ hepatocellular carcinoma (HCC)] and into two interval times (2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS One thousand one hundred and ninty-four [male (M)/female (F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration (490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction (from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst dec-HCV (from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time (289/666, 43.4%), there was a trend towards a decrease after DAAs introduction (from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients (M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival (log-rank test P = 0.02) and delisting rate (P = 0.002) than untreated HCV patients. CONCLUSION Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis.
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Affiliation(s)
- Alberto Ferrarese
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Sarah Shalaby
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Giacomo Zanus
- Hepatobiliary Surgery and Liver Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Paolo Angeli
- Internal Medicine, Department of Medicine, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, via Giustiniani 2, Padua 35128, Italy
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