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Marie MS, Shousha HI, Abdelrazek W, Hassany M, Dabees H, Abdelghafour R, Aboganob WM, Said M. Prediction of hepatic decompensation and hepatocellular carcinoma after direct-acting antiviral therapy in patients with hepatitis C-related liver cirrhosis: a cohort study. EGYPTIAN LIVER JOURNAL 2023; 13:12. [DOI: 10.1186/s43066-023-00247-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 02/19/2023] [Indexed: 03/05/2023] Open
Abstract
AbstractAimThis study aimed to evaluate the rate of hepatic decompensation and de novo HCC and identify their independent factors in HCV genotype 4-infected patients with compensated liver cirrhosis following successful direct-acting antiviral (DAA) therapy.MethodsThis prospective cohort study included 1789 patients with HCV genotype 4-related compensated liver cirrhosis who achieved viral eradication after DAAs. Baseline and follow-up clinical, laboratory, albumin-bilirubin score (ALBI), and abdominal ultrasound were recorded to detect hepatic decompensation and de novo HCC. Logistic regression was performed to evaluate the variables associated with decompensation and HCC.ResultsDuring the 24-month period of follow-up, 184 (10.28%) patients developed hepatic decompensation. Ascites was the commonest presentation. Baseline serum albumin, bilirubin, and platelet count were the independent factors associated with hepatic decompensation (P-values 0.022, 0.03, and < 0.001, respectively). A formula was developed for the prediction of decompensation using these 3 factors (AUC: 0.641 at cutoff 0.1098969 with a sensitivity of 59.9% and specificity of 61.7%). Pre-treatment ALBI score could predict decompensation at cutoff value − 2.5184, AUC 0.609, sensitivity 58.3%, and specificity 59.7%. Post-treatment ALBI score could predict hepatic decompensation after DAA therapy at cutoff value − 2.9521, AUC 0.597, sensitivity 48.1%, and specificity 75.5%. Sixteen (0.9%) patients developed de novo HCC. Age (odds ratio: 1.061, 95%, confidence interval: 1–1.126) and male gender (OR 3.450, 95% CI 1.105–10.769) were the independent factors associated with the development of de novo HCC but not the ALBI score.ConclusionBaseline demographic and laboratory data could predict hepatic decompensation and HCC in patients with compensated liver cirrhosis after successful DAA therapy
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Abdelhamed W, El-Kassas M. Hepatocellular carcinoma and hepatitis C virus treatments: The bold and the beautiful. J Viral Hepat 2023; 30:148-159. [PMID: 36461645 DOI: 10.1111/jvh.13778] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/07/2022] [Accepted: 11/26/2022] [Indexed: 12/04/2022]
Abstract
The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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Dawood RM, El-Meguid MA, Shousha HI, Elsayed A, Nabeel MM, Yosry A, Abdelaziz A, Salum GM. Seven gene signature explores the impact of DAAs on the appearance of hepatocellular carcinoma in HCV infected patients. Heliyon 2022; 8:e10119. [PMID: 36033258 PMCID: PMC9404272 DOI: 10.1016/j.heliyon.2022.e10119] [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: 02/02/2022] [Revised: 04/30/2022] [Accepted: 07/25/2022] [Indexed: 11/03/2022] Open
Abstract
UNLABELLED HCV damages the hepatocytes ending with hepatocellular carcinoma (HCC). The direct-acting antivirals (DAAs) treatment has raised hopes for reducing the incidence of HCC. However, several scientific debate regarding the impact of DAAs on the occurrence of HCC in patients with cirrhosis. We aimed to study the Cirrhosis Risk Score (CRS), several clinical factors and tumor characteristics between patients who developed HCC either with or without DAAs treatment "DAA-exposed HCC patients" and "DAA-unexposed HCC patients". METHODS CRS was assessed via genotyping by allelic discrimination assays in HCV patients who developed de novo HCC (with DAAs (DAA-exposed HCC patients, n = 50), and without DAAs treatment (DAA-unexposed HCC patients, n = 40)). APRI, FIB-4 scores, and tumor characteristics were assessed. RESULTS Around 60% and 48% of DAA-exposed HCC patients and DAA-unexposed HCC patients; respectively had high CRS scores without significant difference. DAA-exposed HCC patients showed elevated Albumin, Hemoglobin and decreased ALT, AST compared with DAA-unexposed HCC patients (P = 0.002, 0.04, <0.001 and 0.006; respectively). FIB4 and APRI didn't reach the statistical difference between the studied groups. DAA-exposed HCC patients have higher overall survival (OS) than DAA-unexposed HCC patients (median: 30 & 15 months; respectively (p = 0.019)). Moreover, no significant differences were observed between the two groups in their focal lesion characteristics. CONCLUSION All studied patients are genetically predisposed to develop HCC. Moreover, DAAs significantly improved the OS and the biochemical parameters. No differences between the two groups were detected regarding their tumor characteristics. Accordingly, the appearance of HCC after treatment is attributed to the natural course of cirrhosis.
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Affiliation(s)
- Reham M. Dawood
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Hend Ibrahim Shousha
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ahmed Elsayed
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mohamed Mahmoud Nabeel
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Abdelaziz
- Department of Endemic Medicine and Hepato-gastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Ghada M. Salum
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, 33 EL Bohouth Street Dokki, Giza, 12622, Egypt
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Badami E, Busà R, Douradinha B, Russelli G, Miceli V, Gallo A, Zito G, Conaldi PG, Iannolo G. Hepatocellular carcinoma, hepatitis C virus infection and miRNA involvement: Perspectives for new therapeutic approaches. World J Gastroenterol 2022; 28:2417-2428. [PMID: 35979260 PMCID: PMC9258280 DOI: 10.3748/wjg.v28.i22.2417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/22/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is the principal etiology of cirrhosis and, ultimately, hepatocellular carcinoma (HCC). At present, approximately 71 million people are chronically infected with HCV, and 10%-20% of these are expected to develop severe liver complications throughout their lifetime. Scientific evidence has clearly shown the causal association between miRNAs, HCV infection and HCC. Although it is not completely clear whether miRNA dysregulation in HCC is the cause or the consequence of its development, variations in miRNA patterns have been described in different liver diseases, including HCC. Many studies have analyzed the importance of circulating miRNAs and their effect on cell proliferation and apoptosis. In this Review, we aim to summarize current knowledge on the association between miRNA, HCV and HCC from a diagnostic point of view, and also the potential implications for therapeutic approaches.
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Affiliation(s)
- Ester Badami
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Bruno Douradinha
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo 90127, Italy
| | - Giovanna Russelli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Vitale Miceli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Giovanni Zito
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
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Sapena V, Enea M, Torres F, Celsa C, Rios J, Rizzo GEM, Nahon P, Mariño Z, Tateishi R, Minami T, Sangiovanni A, Forns X, Toyoda H, Brillanti S, Conti F, Degasperi E, Yu ML, Tsai PC, Jean K, El Kassas M, Shousha HI, Omar A, Zavaglia C, Nagata H, Nakagawa M, Asahina Y, Singal AG, Murphy C, Kohla M, Masetti C, Dufour JF, Merchante N, Cavalletto L, Chemello LL, Pol S, Crespo J, Calleja JL, Villani R, Serviddio G, Zanetto A, Shalaby S, Russo FP, Bielen R, Trevisani F, Cammà C, Bruix J, Cabibbo G, Reig M. Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis. Gut 2022; 71:593-604. [PMID: 33741640 DOI: 10.1136/gutjnl-2020-323663] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/12/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. DESIGN We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. RESULTS Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). CONCLUSION Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
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Affiliation(s)
- Victor Sapena
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Marco Enea
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Sicilia, Italy
| | - Ferran Torres
- Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Ciro Celsa
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Sicilia, Italy
- Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Palermo, Sicilia, Italy
| | - Jose Rios
- Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Giacomo Emanuele Maria Rizzo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Sicilia, Italy
| | - Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy; Université Paris 13, Sorbonne Paris Cité, "Equipe labellisée Ligue Contre le Cancer", F-93206 Saint-Denis; Inserm, UMR-1162, "Génomique fonctionnelle des tumeurs solides", F-75000, Bondy, France
| | - Zoe Mariño
- Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, University of Barcelona, CIBEREHD, Barcelona, Spain
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuya Minami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
- CRC "A.M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Xavier Forns
- Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, University of Barcelona, CIBEREHD, Barcelona, Spain
| | - Hidenori Toyoda
- Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Stefano Brillanti
- Department of Medical and Surgical Sciences (DIMEC), Research Centre for the Study of Hepatitis, University of Bologna, Bologna, Italy
| | - Fabio Conti
- Department of Medical and Surgical Sciences (DIMEC), Research Centre for the Study of Hepatitis, University of Bologna, Bologna, Italy
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy
- CRC "A.M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis, Center Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis, Center Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Kevin Jean
- Laboratoire MESuRS (EA 4628), Conservatoire National Des Arts et Métiers, Paris, France
- Unité PACRI, Institut Pasteur, Conservatoire National des Arts et Métiers, Paris, France
| | - Mohamed El Kassas
- Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Hend Ibrahim Shousha
- Endemic Medicine and Hepato-Gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ashraf Omar
- Endemic Medicine and Hepato-Gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Claudio Zavaglia
- Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milano, Lombardia, Italy
| | - Hiroko Nagata
- Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Institute of Education, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Liver Disease Control, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Caitlin Murphy
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Mohamed Kohla
- Hepatology, National Liver Institute, Shebin El-Kom, Egypt
| | - Chiara Masetti
- Liver and Transplant Unit, Policlinico Tor Vergata, Rome, Italy
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine Inselspital, Bern, Switzerland
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Nicolas Merchante
- Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Seville, Spain
| | - Luisa Cavalletto
- Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases, Padova, Italy
| | - Liliana Lc Chemello
- Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases, Padova, Italy
| | - Stanislas Pol
- l'Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France
| | - Javier Crespo
- Gastroenterology and Hepatology Service, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Spain
- Facultad de Medicina, Universidad de Cantabria, Santander, Cantabria, Spain
| | - Jose Luis Calleja
- Gastroenterology and Hepatology, IDIPHIM, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain
- (CIBEREHD), Instituto de Salud Carlos III, Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Rosanna Villani
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Alberto Zanetto
- Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, University of Padova, Padova, Italy
| | - Sarah Shalaby
- Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, University of Padova, Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, University of Padova, Padova, Italy
| | - Rob Bielen
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Limburg, Belgium
- Department of Gastro-Enterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Limburg, Belgium
| | - Franco Trevisani
- Department of Medical and Surgical Sciences, Semeiotics Unit, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Calogero Cammà
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Sicilia, Italy
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Giuseppe Cabibbo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Sicilia, Italy
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD, Hospital Clinic de Barcelona, Barcelona, Spain
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Kamal A, Elsheaita A, Abdelnabi M. Association between direct-acting antiviral agents in hepatitis C virus treatment and hepatocellular carcinoma occurrence and recurrence: The endless debate. World J Clin Cases 2022; 10:1764-1774. [PMID: 35317156 PMCID: PMC8891795 DOI: 10.12998/wjcc.v10.i6.1764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/05/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Since direct-acting antiviral agents (DAAs) have been introduced into hepatitis C virus treatment, the sustained viral response (SVR) rate has significantly increased to more than 95%. Scientific evidence supports the idea that SVR after interferon therapy has beneficial effects related to cirrhosis progression, resulting in a reduction in the incidence of hepatocellular carcinoma (HCC). However, a significant debate exists related to DAA impact on HCC development. We reviewed the current literature highlighting the controversial data related to DAA association with de novo HCC occurrence or recurrence and possible pathophysiology of HCC related to DAAs. After a review of the published literature, we believe that the current evidence does not confirm or repudiate a higher rate of de novo HCC occurrence or recurrence related to DAA therapy. More trials are needed to determine if there is an association between HCC occurrence or recurrence and DAA or if it is related to preexisting liver cirrhosis.
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Affiliation(s)
- Ahmed Kamal
- Internal Medicine Department, Faculty of Medicine Alexandria University, Alexandria 21131, Egypt
| | - Ahmed Elsheaita
- Clinical and Experimental Internal Medicine Department, Medical Research Institute Alexandria University, Alexandria 21561, Egypt
| | - Mahmoud Abdelnabi
- Clinical and Experimental Internal Medicine Department, Medical Research Institute Alexandria University, Alexandria 21561, Egypt
- Internal Medicine Department, Texas Tech University Health Science Center, Lubbock, TX 79430, United States
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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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Omran M, Fouda M, Abdelwahab AO, Nabeel MM, Abdelaziz AO, Omran D, Shousha HI. P53 is a risk factor of de-novo hepatitis C-related hepatocellular carcinoma treated with direct-acting antivirals: a case-control study. Eur J Gastroenterol Hepatol 2022; 34:220-226. [PMID: 33079785 DOI: 10.1097/meg.0000000000001962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND The mechanisms underlying de-novo hepatocellular carcinoma (HCC) after direct-acting antivirals (DAAs) is still under investigation. This work aims to study P53 and hepatocyte growth factor (HGF) as possible diagnostics of de-novo hepatocellular carcinoma (HCC) following DAAs in comparison to alpha-fetoprotein (AFP). METHOD This case-control study included 166 patients with liver cirrhosis divided into group-1: patients without HCC (n = 50), group-2: patients with de-novo HCC following DAAs, and achieved sustained virological response (n = 50), and group-3: patients with HCC without DAAs (n = 66). P53 antibody and HGF were determined using a quantitative sandwich enzyme immunoassay technique (Cusabio Co, Houston, USA). RESULTS Patients with HCC showed significantly higher HGF. Patients with de-novo HCC following DAAs had significantly higher P53 than HCC without DAAs (P < 0.0001). The multiple logistic regression analysis showed that the P53 levels were significantly associated with susceptibility to de-novo HCC (P value = 0.004). The best overall formula was constructed for HCC diagnosis by entering significant markers into the regression model. A three markers model was developed = (1.22 + AFP X 0.002 + HGF X 0.001 + P53 X 0.001). The medians (percentiles) of combined three markers were 1.8 (1.0-2.1) in liver cirrhosis and 2.2 (2.0-2.9) in all HCC (P < 0.00001). The AUC of combined markers was greater than a single marker. The AUC was 0.87 to differentiate HCC from liver cirrhosis; AUC 0.91 to differentiate de-novo HCC after DAAs from liver cirrhosis. CONCLUSION P53 may serve as a diagnostic marker for de-novo HCC after DAAs therapy. HGF may serve as a diagnostic marker for HCC but not specific for de-novo HCC after DAAs therapy.
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Affiliation(s)
- Mohamed Omran
- Chemistry Department, Faculty of Science, Helwan University
| | - Manar Fouda
- Chemistry Department, Faculty of Science, Helwan University
| | | | | | | | - Dalia Omran
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend Ibrahim Shousha
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Elbaz T, Waked I, El-Akel W, Shaker MK, Abdelaziz AO, Yousif M, El-Bendary M, Zaky S, AbdAllah M, Hassany M, Esmat G, Doss W. Impact of successful HCV treatment using direct acting antivirals on recurrence of well ablated hepatocellular carcinoma. Expert Rev Anti Infect Ther 2022; 20:307-314. [PMID: 34253123 DOI: 10.1080/14787210.2021.1951230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/30/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND There are many contradictory studies that dealt with hepatocellular carcinoma (HCC) recurrence rate of well ablated hepatitis C virus (HCV) related HCC. We aim to assess the recurrence rate of previously ablated HCC in patients who received direct acting antiviral (DAA) for their HCV. RESEARCH DESIGN AND METHODS This is a retrospective data analysis of 523 HCV patients who have a history of successfully ablated HCC and eligible for HCV treatment. Retrieval was done to demographic/clinical data, HCV pretreatment investigations, HCV treatment outcome. Follow up for survival and HCC recurrence was done every 3 months using abdominal ultrasound and alfa-fetoprotein. RESULTS Mean age was 53.83 years. Sofosbuvir/daclatasvir/ribavirin was the most used regimen (35.4%) with 438 patients (83.7%) achieved sustained virologic response (SVR). The median duration for surveillance was 159 weeks. Hundred and five patients developed recurrent HCC, with a crude recurrence rate of 20.1%. There was no difference between HCV responders and non-responders in crude recurrence rate (p = 0.94) but HCC developed earlier in non-responders (p = <0.01). CONCLUSION Recurrence of HCC remains a threat in HCV patients even after achieving an SVR. Implementation of long-term surveillance programs is highly recommended.
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Affiliation(s)
- Tamer Elbaz
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Imam Waked
- Department of Hepatology, National Liver Institute, Menoufiya University, Menoufiya, Egypt
| | - Wafaa El-Akel
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Kamal Shaker
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Monkez Yousif
- Internal Medicine Department, Zagazig University, Sharkia, Egypt
| | - Mahmoud El-Bendary
- Department of Tropical Medicine and Hepatology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Samy Zaky
- Department of Hepatogastroenterology and Infectious Diseases, Al-Azhar University, Cairo, Egypt
| | - Mohamed AbdAllah
- Medical Research Division, National Research Center, Giza, Egypt
| | - Mohamed Hassany
- Tropical Medicine Department, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | - Gamal Esmat
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Wahid Doss
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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10
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Carissimi F, Barbaglia MN, Salmi L, Ciulli C, Roccamatisi L, Cordaro G, Mallela VR, Minisini R, Leone BE, Donadon M, Torzilli G, Pirisi M, Romano F, Famularo S. Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment. World J Gastrointest Surg 2021; 13:967-978. [PMID: 34621473 PMCID: PMC8462072 DOI: 10.4240/wjgs.v13.i9.967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/25/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as "seeds" in peripheral blood, then reach the target organ as dormant cells which could be subsequently "awakened" and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.
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Affiliation(s)
- Francesca Carissimi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | | | - Livia Salmi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Cristina Ciulli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Linda Roccamatisi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Giuseppe Cordaro
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Venkata Ramana Mallela
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Biagio Eugenio Leone
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Unit of Pathology, San Gerardo Hospital, Monza 20900, Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Medicine and Surgery, University of Milan-Bicocca, Monza 20900, Italy
| | - Simone Famularo
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
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11
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Tani J, Senoh T, Moriya A, Ogawa C, Deguchi A, Sakamoto T, Takuma K, Nakahara M, Oura K, Tadokoro T, Mimura S, Fujita K, Yoneyama H, Kobara H, Morishita A, Himoto T, Tsutsui A, Nagano T, Takaguchi K, Masaki T. Long-Term Outcomes and Evaluation of Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Eradication by Direct-Acting Antiviral Treatment: All Kagawa Liver Disease Group (AKLDG) Study. Cancers (Basel) 2021; 13:cancers13092257. [PMID: 34066708 PMCID: PMC8125844 DOI: 10.3390/cancers13092257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/09/2022] Open
Abstract
There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924-8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016-1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
- Correspondence: ; Tel.: +81-87-891-2156
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kagawa 769-1695, Japan;
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Kagawa 760-0017, Japan;
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Kagawa 763-8502, Japan;
| | - Teppei Sakamoto
- Department of Internal Medicine, Yashima General Hospital, Kagawa 761-0816, Japan;
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa 761-0123, Japan;
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
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Wang CC, Tseng KC, Tzeng IS, Kao JH. The impact of cytokine change after hepatitis C virus clearance by direct antiviral agents on the risk of hepatocellular carcinoma. J Formos Med Assoc 2021; 120:965-973. [PMID: 33129621 DOI: 10.1016/j.jfma.2020.10.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/30/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE De novo and early recurrent hepatocellular carcinoma (HCC) have been observed in clinical practice after direct antiviral agents (DAA) treatment. The study aims to investigate the change of cytokines and growth factors after hepatitis C virus (HCV) clearance by DAAs and their impact on the risk of HCC development. METHODS The chronic hepatitis C (CHC) patients with or without HCC who received DAA treatment were prospectively enrolled. The cytokines and growth factors were measured using Bio-Plex Pro™ Human Cytokine 27-plex Assay before and 12 weeks off DAA treatment. RESULTS A total of 37 patients were enrolled for final analysis. There were 11 males (29.7%) and 26 females (70.3%). The mean age was 67.39 ± 10.48 years. 11 (29.7%) patients were HCV-related HCC patients. The HCV genotype included genotype 2 in 26 patients and genotype 1b in 10 patients, and genotype 6 in 1. Among them, 35 (94.6%) patients achieved sustained virologic response (SVR). Two patients with HCC failed to DAA treatment. In HCV-related HCC patients, serum IP-10 level significantly declined after HCV clearance, but no difference in five growth factors including G-CSF, GM-CSF, basic FGF, PDGF-BB, and VEGF. Several cytokines including IP-10 significantly declined after HCV clearance in CHC patients. CONCLUSION This study showed only serum IP-10 level, a risk factor of HCC, was significantly declined after HCV clearance and no change in the markers of growth factors in HCV-related HCC patients, suggesting no promotion of HCC using DAA treatment for HCV-related HCC patients.
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Affiliation(s)
- Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Kuo-Chih Tseng
- Department of Gastroenterology, Da-Lin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - I-Shiang Tzeng
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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13
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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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14
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Andreone P, Di Marco V, Gaeta GB, Fagiuoli S, Vukotic R, Craxì A. Current and forthcoming perspectives in linkage to care of hepatitis C virus infection: Assessment of an Italian focus group. Dig Liver Dis 2019; 51:915-921. [PMID: 31031174 DOI: 10.1016/j.dld.2019.03.033] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/06/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) remains a significant public health problem and is one of the major causes of chronic liver disease worldwide. In recent years many new tools to facilitate widespread HCV screening and new therapeutic options with excellent efficacy and tolerability profiles and cost lowering policies have become available. To fully utilise these new tools, the link between local and specialist centres for the management of HCV infection must be reinforced. In order to GAIN further insight into these aspects, with a particular focus on the Italian scenario, a group of experts met to discuss relevant aspects and open issues on chronic HCV. As a summary of that meeting, the following aspects are here overviewed: (i) global situation of HCV; (ii) screening, diagnosis and indications for the treatment of HCV; (iii) the Italian situation of HCV referrals; (iv) 'hard to reach' patients; (v) treatment of HCV with extrahepatic manifestations; (vi) treatment of patients with advanced cirrhosis. It is the intention of the expert panel to further promote widespread screening and eradication policies that should be accompanied by greater interaction, by attempting to involve all healthcare providers in an organised process to facilitate linkage to care of patients with HCV infections.
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Affiliation(s)
- Pietro Andreone
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
| | - Vito Di Marco
- Unit of Gastroenterology, PROMISE Department, University of Palermo, Palermo, Italy.
| | - Giovanni Battista Gaeta
- Department of Mental and Physical Health and Preventive Medicine, Infectious Diseases, Campania University "Luigi Vanvitelli", Napoli, Italy.
| | - Stefano Fagiuoli
- Department of Gastroenterology, Hepatology and Liver Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy.
| | - Ranka Vukotic
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
| | - Antonio Craxì
- Gastroenterology and Liver Unit, DiBiMIS, University of Palermo, Palermo, Italy.
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15
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El Kassas M, Elbaz T, Salaheldin M, Abdelsalam L, Kaseb A, Esmat G. Impact of treating chronic hepatitis C infection with direct-acting antivirals on the risk of hepatocellular carcinoma: The debate continues - A mini-review. J Adv Res 2019; 17:43-48. [PMID: 31193326 PMCID: PMC6526204 DOI: 10.1016/j.jare.2019.03.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/26/2019] [Accepted: 03/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus clearance is expected in more than 95% of patients treated with direct-acting antivirals (DAAs). However, an extensive debate about the impact of DAAs on the development of hepatocellular carcinoma (HCC) is currently ongoing. This review aimed to explore currently available evidence about the relationship between DAAs and HCC development. The American studies and some European studies clearly showed no relation, while the Japanese and Egyptian studies and the other European studies showed an increased risk of developing HCC after DAA exposure. These conflicting results may be due to geographical and ethnic variations and differences in the design and inclusion criteria among the studies. After reviewing the data from these different studies, it seems that some patients are at increased risk of developing HCC after DAA exposure. Identifying those at increased risk is very important for the management of HCC in light of the potentially major consequences of HCC for the patients' quality of life and the subsequent major burden imposed on healthcare resources.
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Affiliation(s)
- Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Tamer Elbaz
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Salaheldin
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Lobna Abdelsalam
- Genome Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Texas, USA
| | - Gamal Esmat
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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16
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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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17
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Preda CM, Baicus C, Sandra I, Oproiu A, Manuc T, Constantinescu I, Gavrila D, Diculescu M, Dumitru R, Vasilescu C, Tieranu C, Istratescu D, Voiosu T, Manuc M. Recurrence rate of hepatocellular carcinoma in patients with treated hepatocellular carcinoma and hepatitis C virus-associated cirrhosis after ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin therapy. United European Gastroenterol J 2019; 7:699-708. [PMID: 31210948 DOI: 10.1177/2050640619841254] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 03/08/2019] [Indexed: 12/29/2022] Open
Abstract
Introduction Recent studies have suggested a higher recurrence rate of hepatocellular carcinoma (HCC) in patients with a history of HCC and hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antiviral (DAA) agents. Material and methods We conducted a prospective analysis of 24 patients with HCV-associated cirrhosis and treated HCC who received ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin for 12 weeks. Prior therapies for HCC included resection (9/24 patients), radiofrequency ablation (RFA) (7/24) and trans-arterial chemoembolization (TACE) (8/24). All patients were eligible for treatment if they had no HCC recurrence 6 months after their last procedure. A control group was defined. All patients were followed every 6 months, with dynamic computed tomography and/or magnetic resonance imaging. Results The sustained virological response rate per protocol was 21/24 (87.5%). The study group included 14 (59%) males, median age 64 years (51-77), 50% with associated non-alcoholic steatohepatitis and 24% with Child-Pugh A6 points. HCC recurrence rate/100 patient-years was lower in the DAA-HCC group versus control: 5.5 versus 24.6% patient-years for the resection+RFA group (p = 0.044), respectively, and 18.6 versus 72.7% patient-years for TACE group (p = 0.002). Survival without recurrence was higher in the resection+RFA group (45 compared to 18 months (p < 0.001)) and also in the TACE group (44 compared to 11.5 months (p = 0.002)). Conclusions DAA therapy significantly reduced the recurrence rate of HCC and improved survival without recurrence in patients with treated HCV-associated HCC.
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Affiliation(s)
- Carmen M Preda
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Cristian Baicus
- Internal Medicine Department, Colentina Hospital, Bucharest, Romania
| | - Irina Sandra
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Alexandru Oproiu
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Teodora Manuc
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Ileana Constantinescu
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Daniel Gavrila
- Surgery Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Mircea Diculescu
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Radu Dumitru
- Radiology Department, Clinic Fundeni Institute, Bucharest, Romania
| | | | - Cristian Tieranu
- Gastroenterology and Hepatology Department, Elias Emergency Hospital, Bucharest, Romania
| | - Doina Istratescu
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
| | - Theodor Voiosu
- Internal Medicine Department, Colentina Hospital, Bucharest, Romania
| | - Mircea Manuc
- Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania
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18
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Guarino M, Viganò L, Ponziani FR, Giannini EG, Lai Q, Morisco F. Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: Literature review and risk analysis. Dig Liver Dis 2018; 50:1105-1114. [PMID: 30170908 DOI: 10.1016/j.dld.2018.08.001] [Citation(s) in RCA: 35] [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: 05/26/2018] [Revised: 07/26/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023]
Abstract
Although studies suggest decreased incident hepatocellular carcinoma (HCC) after treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, data are conflicting regarding risk and aggressiveness of recurrence in patients who have a history of treated HCC. This review analyses data available in literature in order to elucidate the impact of DAAs on the risk of HCC recurrence after successful treatment of the tumor. Overall 24 papers were identified. The available data cannot be considered definitive, but the initial alarmist data indicating an increased risk of recurrence have not been confirmed by most subsequent studies. The suggested aggressive pattern (rapid growth and vascular invasion) of tumor recurrence after DAAs still remains to be confirmed. Several limitations of the available studies were highlighted, and should drive future researches. The time-to-recurrence should be computed since the last HCC treatment and results stratified for cirrhosis and sustained viral response. Any comparison with historical series is of limited interest because of a number of biases affecting these studies and differences between enrolled patients. Prospective intention-to-treat analyses will be probably the best contribution to drive clinical practice, provided that a randomized trial can be difficult to design.
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Affiliation(s)
- Maria Guarino
- Dept. of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
| | - Luca Viganò
- Dept. of Surgery, Division of Hepatobiliary and General Surgery, Humanitas Clinical and Research Hospital, Humanitas University, Rozzano, Milan, Italy
| | - Francesca Romana Ponziani
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Polyclinic Foundation "Agostino Gemelli", IRCCS, Catholic University of Rome, Rome, Italy.
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Polyclinic Hospital "San Martino", Genoa, Italy.
| | - Quirino Lai
- Hepato-bilio-pancreatic and Liver Transplant Unit, Dept. of Surgery, Sapienza University of Rome, Rome, Italy
| | - Filomena Morisco
- Dept. of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
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19
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Omran D, Alboraie M, Zayed RA, Wifi MN, Naguib M, Eltabbakh M, Abdellah M, Sherief AF, Maklad S, Eldemellawy HH, Saad OK, Khamiss DM, El Kassas M. Towards hepatitis C virus elimination: Egyptian experience, achievements and limitations. World J Gastroenterol 2018; 24:4330-4340. [PMID: 30344418 PMCID: PMC6189850 DOI: 10.3748/wjg.v24.i38.4330] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/13/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Worldwide, more than one million people die each year from hepatitis C virus (HCV) related diseases, and over 300 million people are chronically infected with hepatitis B or C. Egypt used to be on the top of the countries with heavy HCV burden. Some countries are making advances in elimination of HCV, yet multiple factors preventing progress; remain for the majority. These factors include lack of global funding sources for treatment, late diagnosis, poor data, and inadequate screening. Treatment of HCV in Egypt has become one of the top national priorities since 2007. Egypt started a national treatment program intending to provide cure for Egyptian HCV-infected patients. Mass HCV treatment program had started using Pegylated interferon and ribavirin between 2007 and 2014. Yet, with the development of highly-effective direct acting antivirals (DAAs) for HCV, elimination of viral hepatitis has become a real possibility. The Egyptian National Committee for the Control of Viral Hepatitis did its best to provide Egyptian HCV patients with DAAs. Egypt adopted a strategy that represents a model of care that could help other countries with high HCV prevalence rate in their battle against HCV. This review covers the effects of HCV management in Egyptian real life settings and the outcome of different treatment protocols. Also, it deals with the current and future strategies for HCV prevention and screening as well as the challenges facing HCV elimination and the prospect of future eradication of HCV.
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Affiliation(s)
- Dalia Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo 11651, Egypt
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo 11651, Egypt
| | - Rania A Zayed
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo 11651, Egypt
| | - Mohamed-Naguib Wifi
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 11599, Egypt
| | - Mervat Naguib
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 11599, Egypt
| | - Mohamed Eltabbakh
- Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Mohamed Abdellah
- Department of Internal Medicine, Al-Azhar University, Cairo 11651, Egypt
| | - Ahmed Fouad Sherief
- Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Sahar Maklad
- National Hepatology and Tropical Medicine Research Institute, Cairo 11599, Egypt
| | - Heba Hamdy Eldemellawy
- Department of Internal Medicine, Faculty of Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | | | - Doaa Mohamed Khamiss
- Department of Clinical and Chemical Pathology, El-monera hospital, Ministry of Health, Cairo 11562, Egypt
| | - Mohamed El Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo 11599, Egypt
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20
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Gigi E, Lagopoulos VI, Bekiari E. Hepatocellular carcinoma occurrence in DAA-treated hepatitis C virus patients: Correlated or incidental? A brief review. World J Hepatol 2018; 10:595-602. [PMID: 30310537 PMCID: PMC6177564 DOI: 10.4254/wjh.v10.i9.595] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/25/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) chronic infection induces liver fibrosis and cirrhosis but is also responsible for a significant portion of hepatocellular carcinoma (HCC) occurrence. Since it was recognized as a causative factor of chronic hepatitis, there have been multiple efforts towards viral eradication, leading to the first-generation HCV treatment that was based on interferon (IFN)-αand its analogs, mainly PEGylated interferon-α (PEG IFNα). Sustained virological response (SVR), defined as the absence of detectable RNA of HCV in blood serum for at least 24 wk after discontinuing the treatment, was accepted as a marker of viral clearance and was achieved in approximately one-half of patients treated with PEG IFNα regimens. Further research on the molecular biology of HCV gave rise to a new generation of drugs, the so-called direct antiviral agents (DAAs). DAA regimens, as implied by their name, interfere with the HCV genome or its products and have high SVR rates, over 90%, after just 12 wk of per os treatment. Although there are no questions about their efficacy or their universality, as they lack the contraindication for advanced liver disease that marks PEG IFNα, some reports of undesired oncologic outcomes after DAA treatment raised suspicions about possible interference of this treatment in HCC development. The purpose of the present review is to investigate the validity of these concerns based on recent clinical studies, summarize the mechanisms of action of DAAs and survey the updated data on HCV-induced liver carcinogenesis.
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Affiliation(s)
- Eleni Gigi
- 2nd Internal Medicine Department, Aristotle University Medical School, Hippokrateio General Hospital, Thessaloniki 54642, Greece
| | - Vasileios I Lagopoulos
- 5th Surgical Department, Aristotle University Medical School, Hippokrateio General Hospital, Thessaloniki 54642, Greece
| | - Eleni Bekiari
- 2nd Internal Medicine Department, Aristotle University Medical School, Hippokrateio General Hospital, Thessaloniki 54642, Greece
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