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Fassio E, Colombato L, Gualano G, Perez S, Puga-Tejada M, Landeira G. Hepatocellular Carcinoma After HCV Eradication with Direct-Acting Antivirals: A Reappraisal Based on New Parameters to Assess the Persistence of Risk. Cancers (Basel) 2025; 17:1018. [PMID: 40149352 PMCID: PMC11940336 DOI: 10.3390/cancers17061018] [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: 02/25/2025] [Revised: 03/12/2025] [Accepted: 03/16/2025] [Indexed: 03/29/2025] Open
Abstract
Approximately 95% of patients with chronic hepatitis C achieve viral eradication through direct-acting antiviral (DAA) treatment. Ensuing clinical benefits include halting liver fibrosis, thereby reducing the need for liver transplantation, and decreasing both liver-related and overall mortality. It is well established that, although ameliorated, the risk of developing hepatocellular carcinoma (HCC) persists, particularly among patients with pre-treatment advanced fibrosis/cirrhosis. Current guidelines recommend indefinite HCC surveillance in these patients. However, a recent Markov model evaluation shows that HCC surveillance is cost-effective only for patients with cirrhosis but not so for those with F3 fibrosis, a finding which points out the need to better define the risk of HCC in hepatitis C patients after cure and further characterize pre- and post-treatment factors that might affect the incidence of HCC in this setting. We reviewed the literature analyzing this aspect. Here we summarize the main findings: male gender and older age are independent predictors of increased risk of post-cure HCC development. Moreover, non-invasive tests for hepatic fibrosis, namely FIB4, APRI, and liver stiffness, measured before and after treatment and their post-therapy change, contribute to better stratifying the risk of HCC occurrence. Furthermore, low serum albumin, as well as an AFP above 7 ng/mL prior to and after DAA therapy, also constitute independent predictors of HCC development. Considering these findings, we propose to classify patients with HCV viral eradication and advanced fibrosis/cirrhosis into groups of low, medium, or high risk of HCC and to adopt adequate surveillance strategies for each group, including protocols for abbreviated magnetic resonance imaging (MRI) for those at the highest risk.
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Affiliation(s)
- Eduardo Fassio
- Liver Section, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires 1684, Argentina; (S.P.); (G.L.)
| | - Luis Colombato
- Hospital Británico de Buenos Aires, Buenos Aires 1280, Argentina;
| | - Gisela Gualano
- Hospital Regional Dr. Ramón Carrillo, Santiago del Estero 4200, Argentina;
| | - Soledad Perez
- Liver Section, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires 1684, Argentina; (S.P.); (G.L.)
| | - Miguel Puga-Tejada
- Instituto Ecuatoriano de Enfermedades Digestivas, Guayaquil 090505, Ecuador;
| | - Graciela Landeira
- Liver Section, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires 1684, Argentina; (S.P.); (G.L.)
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Sangro B, Argemi J, Ronot M, Paradis V, Meyer T, Mazzaferro V, Jepsen P, Golfieri R, Galle P, Dawson L, Reig M. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol 2025; 82:315-374. [PMID: 39690085 DOI: 10.1016/j.jhep.2024.08.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 12/19/2024]
Abstract
Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.
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Shiha G, Hassan A, Mousa N, El-Domiaty N, Mikhail N, Gameaa R, Kobtan A, El Bassat H, Sharaf-Eldin M, Waked I, Eslam M, Soliman R. Individualized HCC surveillance using risk stratification scores in advanced fibrosis and cirrhotic HCV patients who achieved SVR: Prospective study. Aliment Pharmacol Ther 2025; 61:99-108. [PMID: 39313490 DOI: 10.1111/apt.18291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/09/2024] [Accepted: 09/09/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Several HCC risk stratification scores were developed; however, none has been prospectively validated. The primary aim is to validate the clinical utility of six HCC risk scores in large prospective study of F3-4 patients achieving SVR following DAAs according to EASL guidelines. The secondary aim is to explore whether individualized risk stratification improves detection of HCC at early stages amenable to curative treatment. METHODS This prospective study included two cohorts: Egyptian Liver Research Institute and Hospital (ELRIAH) cohort of 463 chronic HCV patients with advanced liver disease (F3 and F4) achieved SVR with a follow-up every 6 months according to EASL guidelines using 6 simple HCC risk scores and Tanta cohort of 492 comparable patients where individualized surveillance intervals were tailored based on HCC risk assessments using GES score as follows: low-risk patients were followed yearly, intermediate-risk every 6 months and high-risk every 2-3 months. RESULTS All scores, except Watanabe post, successfully stratified patients into low-, intermediate- and high-risk groups, with log-rank p-value of 0.001 and Harrell's C ranging from 0.669 to 0.728. Clinical utility of these scores revealed that the highest percentage of patients classified as low risk was 42.5% using the GES, while the lowest was 8.9% using the aMAP. ELRIAH cohort, 25 patients developed HCC with 52% diagnosed at BCLC 0 and A. Tanta cohort, 35 patients developed HCC, with 80% diagnosed at BCLC 0 and A. CONCLUSION Individualized risk stratification using HCC risk scores was associated with improved early-stage detection and receipt of curative treatment.
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Affiliation(s)
- Gamal Shiha
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
| | - Ayman Hassan
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
- Higher Institute of Applied Medical Sciences, Mansoura, Egypt
| | - Nasser Mousa
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nada El-Domiaty
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Nabiel Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
- Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Reham Gameaa
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abdelrahman Kobtan
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hanan El Bassat
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Sharaf-Eldin
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Imam Waked
- National Liver Institute, Menofia University, Menofia, Egypt
| | - Mohamed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| | - Riham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
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Lv GJ, Ji D, Yu L, Chen HY, Chen J, He M, Wang WC, Wang HB, Tsang C, Wang J, Yu ML, Lau G. Risk of hepatocellular carcinoma occurrence after antiviral therapy for patients with chronic hepatitis C Infection: a systematic review and meta-analysis. Hepatol Int 2024; 18:1459-1471. [PMID: 38965190 DOI: 10.1007/s12072-024-10700-7] [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: 01/23/2024] [Accepted: 05/11/2024] [Indexed: 07/06/2024]
Abstract
BACKGROUND AND AIMS The risk of hepatocellular carcinoma (HCC) occurrence following antiviral therapy in patients with chronic hepatitis C (CHC) remains unclear. The current study aims to compare: (1) the HCC occurrence rate following sustained virological response (SVR) versus non-response (NR); (2) the HCC occurrence rate following direct-acting antiviral (DAA) therapy versus interferon (IFN)-based therapy, and (3) the HCC occurrence rate in SVR patients with or without cirrhosis. METHODS A search was performed for articles published between January 2017 and July 2022. Studies were included if they assessed HCC occurrence rate in CHC patients following anti-HCV therapy. Random effects meta-analysis was used to synthesize the results from individual studies. RESULTS A total of 23 studies including 29,395 patients (IFN-based = 6, DAA = 17; prospective = 10, retrospective = 13) were included in the review. HCC occurrence was significantly lower in CHC with SVR (1.54 per 100 person-years (py, 95% CI 1.52, 1.57) than those in non-responders (7.80 py, 95% CI 7.61, 7.99). Stratified by HCV treatment regimens, HCC occurrence following SVR was 1.17 per 100 py (95% CI 1.11, 1.22) and 1.60 per 100 py (95% CI 1.58, 1.63) in IFN- and DAA treatment-based studies. HCC occurrence was 0.85 per 100 py (95% CI 0.85, 0.86) in the non-cirrhosis population and rose to 2.47 per 100 py (95% CI 2.42, 2.52) in the cirrhosis population. Further meta-regression analysis showed that treatment types were not associated with a higher HCC occurrence rate, while cirrhosis status was an important factor of HCC occurrence rate. CONCLUSION HCC occurrence was significantly lower in the SVR population than in the NR population. HCC risk following SVR occurred three times more frequently in patients with cirrhosis than patients without cirrhosis. However, we found no significant difference in HCC occurrence risk following SVR between DAA and IFN therapies. CLINICAL TRIAL NUMBER CRD42023473033.
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Affiliation(s)
- Gui-Ji Lv
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Peking University 302 Clinical Medical School, Beijing, 100039, China
| | - Dong Ji
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Peking University 302 Clinical Medical School, Beijing, 100039, China
- Chinese PLA Medical School, Beijing, 100853, China
| | - Lingxiang Yu
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Hong-Yan Chen
- Hospital of North China Electric Power University, Beijing, 102206, China
| | - Jing Chen
- JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, 9 Queen's Road Central, Central, Hong Kong SAR, China
| | - Mengwen He
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
- Peking University 302 Clinical Medical School, Beijing, 100039, China
| | | | - Hong-Bo Wang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Christopher Tsang
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, 9 Queen's Road Central, Central, Hong Kong SAR, China
| | - Jianjun Wang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung, 807, Taiwan.
| | - George Lau
- Chinese PLA Medical School, Beijing, 100853, China.
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, 9 Queen's Road Central, Central, Hong Kong SAR, China.
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenlin Road, Shanghai, 200032, China.
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Ohama H, Hiraoka A, Tada T, Kariyama K, Itobayashi E, Tsuji K, Ishikawa T, Toyoda H, Hatanaka T, Kakizaki S, Naganuma A, Tada F, Tanaka H, Nakamura S, Nouso K, Tanaka K, Kumada T. Changes in clinical outcomes in Japanese patients with hepatocellular carcinoma due to hepatitis C virus following the development of direct-acting antiviral agents. J Gastroenterol Hepatol 2024; 39:1394-1402. [PMID: 38602340 DOI: 10.1111/jgh.16553] [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: 12/26/2023] [Revised: 03/11/2024] [Accepted: 03/20/2024] [Indexed: 04/12/2024]
Abstract
BACKGROUND AND AIM Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development. METHODS A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n = 1169) and post-DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed. RESULTS Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P < 0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P < 0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P = 1.0). CONCLUSION The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients.
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Affiliation(s)
- Hideko Ohama
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
- Department of Gastroenterology, Takarazuka City Hospital, Hyogo, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Kazuya Kariyama
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Gunma, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Fujimasa Tada
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hironori Tanaka
- Department of Gastroenterology, Takarazuka City Hospital, Hyogo, Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Kazuhiro Nouso
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Kazunari Tanaka
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
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Sano T, Amano K, Ide T, Isoda H, Honma Y, Morita Y, Yano Y, Nakamura H, Itano S, Miyajima I, Shirachi M, Kuwahara R, Ohno M, Kawaguchi T, Tsutsumi T, Nakano D, Arinaga-Hino T, Kawaguchi M, Eguchi Y, Torimura T, Takahashi H, Harada M, Kawaguchi T. Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study. Hepatol Res 2024; 54:326-335. [PMID: 37975277 DOI: 10.1111/hepr.13993] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/14/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023]
Abstract
AIMS Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.
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Affiliation(s)
- Tomoya Sano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Fukuoka Consulting and Support Center for Liver Diseases, Kurume, Japan
- Department of Gastroenterology, Kurume University Medical Center, Kurume, Japan
| | - Hiroshi Isoda
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuichi Honma
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yasuyo Morita
- Department of Gastroenterology, Nagata Hospital, Yanagawa, Japan
| | - Yoichi Yano
- Division of Gastroenterology, Department of Medicine, Saga Central Hospital, Saga, Japan
| | - Hiroki Nakamura
- Department of Gastroenterology, Shin Koga Hospital, Kurume, Japan
| | - Satoshi Itano
- Department of Gastroenterology, Kurume Chuo Hospital, Kurume, Japan
| | - Ichiro Miyajima
- Department of Gastroenterology, Kumamoto Central Hospital, Kikuchi, Japan
| | - Miki Shirachi
- Department of Gastroenterology, Chikugo City Hospital, Chikugo, Japan
| | - Reiichiro Kuwahara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Department of Gastroenterology, Oita Saiseikai Hita Hospital, Hita, Japan
| | - Miki Ohno
- Department of Gastroenterology and Hepatology, Yanagawa Hospital, Yanagawa, Japan
| | - Toshihiro Kawaguchi
- Division of Gastroenterology, Department of Medicine, Social Insurance Tagawa Hospital, Tagawa, Japan
| | - Tsubasa Tsutsumi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Machiko Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yuichiro Eguchi
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
- Loco Medical General Institute, Ogi, Japan
| | - Takuji Torimura
- Department of Gastroenterology, Omuta City Hospital, Omuta, Japan
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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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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Elbahrawy A, Atalla H, Mahmoud AA, Eliwa A, Alsawak A, Alboraie M, Madian A, Alashker A, Mostafa S, Alwassief A, Aly HH. Prediction and surveillance of de novo HCC in patients with compensated advanced chronic liver disease after hepatitis C virus eradication with direct antiviral agents. FRONTIERS IN VIROLOGY 2023; 3. [DOI: 10.3389/fviro.2023.1227317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The risk of hepatocellular carcinoma (HCC) diminishes in patients with hepatitis C virus (HCV)-related advanced chronic liver disease after virological cure. However, despite viral clearance, HCV-induced epigenetic alterations, immune dysregulations, and hepatic parenchymal injuries remain, contributing to de novo HCC occurrence. While HCC incidence is low (0.45 – 0.5%) in patients with advanced fibrosis (F3), the presence of liver cirrhosis and clinically significant portal hypertension increases the HCC risk. The cost-effectiveness of lifelong HCC surveillance in patients with compensated advanced chronic liver disease (cACLD) has sparked debate, raising questions about the most reliable noninvasive tests and stratification models for predicting HCC in patients with sustained virological response (SVR). Furthermore, identifying cACLD patients who may not require long-term HCC surveillance after SVR remains crucial. Several HCC risk stratification scores have been suggested for patients with cACLD, and emerging evidence supports individualized care based on personalized risk assessments. This review focuses on revising the pretreatment and posttreatment predictors of HCC, as well as the indications for HCC surveillance in cACLD patients treated with direct-acting antivirals.
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Toyoda H, Kikuchi K. Management of dialysis patients with hepatitis C virus in the era of direct-acting antiviral therapy. Ther Apher Dial 2023; 27:831-838. [PMID: 37217295 DOI: 10.1111/1744-9987.14003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/24/2023] [Accepted: 05/06/2023] [Indexed: 05/24/2023]
Abstract
The clinical use of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection has dramatically changed management of patients with HCV liver disease since 2014; this is also true for patients undergoing dialysis. Due to the high tolerability and antiviral efficacy of anti-HCV therapy, most dialysis patients with HCV infection should currently be candidates for this treatment. Many patients with HCV antibodies no longer have HCV infection, and it is difficult to identify patients with actual HCV infection based only on HCV antibody assays. Despite the high rate of successful HCV eradication, the risk of liver-related events such as hepatocellular carcinoma (HCC), the major complication of HCV infection, persists even after HCV cure, and patients at risk of HCC should undergo continuous HCC surveillance. Finally, the rarity of HCV reinfection and the survival benefit of HCV eradication in dialysis patients should be explored in further studies.
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Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Kan Kikuchi
- Division of Nephrology, Shimoochiai Clinic, Tokyo, Japan
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Luan CH, Su PS, Chu CJ, Lin CC, Su CW, Lee SD, Wang YJ, Lee FY, Huang YH, Hou MC. Residual risk of hepatocellular carcinoma development for chronic hepatitis C patients treated by all oral direct-acting antivirals with sustained virological response. J Chin Med Assoc 2023; 86:795-805. [PMID: 37466658 DOI: 10.1097/jcma.0000000000000965] [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: 07/20/2023] Open
Abstract
BACKGROUND The treatment of chronic hepatitis C (CHC) infection underwent a significant transformation with the introduction of all-oral direct-acting anti-virals (DAAs). These medications offered a high success rate in treatment, shorter duration, good tolerability, and expanded treatment options. However, a residual risk of hepatocellular carcinoma (HCC) development remained for a few patients even after achieving sustained virological response (SVR). To date, there is a lack of real-world data on evaluating risk factors associated with de novo HCC in CHC patients post-SVR, particularly in Taiwan. METHODS Between January 2017 and December 2019, a total of 671 consecutive CHC patients who achieved SVR after receiving DAAs were included for analysis. Patients with a history of HCC or liver transplantation prior to DAAs, a short follow-up period (<1 year), or treatment failure with DAAs were excluded. The primary outcome was the development of HCC following the initiation of DAAs. Variables associated with the primary outcome were assessed using multivariate Cox proportional hazards models. RESULTS The mean age of the enrolled patients was 65.1 ± 12.8 years, with 39.6% of them being male. Among the patients, 30.6% had advanced (F3-4) fibrosis, and the median follow-up period was 2.90 years. The cumulative incidence of HCC in CHC patients post-SVR12 was 1.6% at 1 year, 4.4% at 2 years, 4.8% at 3 years, 5.3% at 4 years, and 6.1% at 4.8 years, respectively. Variables independently associated with de novo HCC were advanced liver fibrosis (hazard ratio [HR] = 6.745; 95% CI = 1.960-23.218; p = 0.002), end-of-treatment 12 weeks (EOT 12 ) alpha-fetoprotein (AFP) >7 ng/mL (HR = 3.059; 95% CI = 1.215-7.669; p = 0.018), EOT 12 albumin-bilirubin (ALBI) grade ≥ 2 (HR = 2.664; 95% CI = 1.158-6.128; p = 0.021), and body mass index (BMI) ≥ 25 kg/m 2 (HR = 2.214; 95% CI = 1.011-4.852; p = 0.047). CONCLUSION Despite achieving viral clearance with DAAs, CHC patients still face a residual risk of de novo HCC. Establishing a risk stratification model based on independent variables could facilitate the prediction of future HCC development and enhance screening strategies.
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Affiliation(s)
- Chih-Hsuan Luan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pin-Shuo Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chi-Jen Chu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chung-Chi Lin
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chien-Wei Su
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
| | - Yuan-Jen Wang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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11
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Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology 2023; 78:319-362. [PMID: 36082510 PMCID: PMC9995677 DOI: 10.1002/hep.32779] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/25/2022] [Accepted: 08/28/2022] [Indexed: 12/08/2022]
Abstract
Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.
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Affiliation(s)
- Yi-Te Lee
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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12
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Watanabe T, Tokumoto Y, Joko K, Michitaka K, Horiike N, Tanaka Y, Hiraoka A, Tada F, Ochi H, Kisaka Y, Nakanishi S, Yagi S, Yamauchi K, Higashino M, Hirooka K, Morita M, Okazaki Y, Yukimoto A, Hirooka M, Abe M, Hiasa Y. Simple new clinical score to predict hepatocellular carcinoma after sustained viral response with direct-acting antivirals. Sci Rep 2023; 13:8992. [PMID: 37268672 DOI: 10.1038/s41598-023-36052-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/28/2023] [Indexed: 06/04/2023] Open
Abstract
The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime, 790-8524, Japan
| | - Kojiro Michitaka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime, 790-0024, Japan
| | - Norio Horiike
- Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime, 799-1502, Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime, 790-0067, Japan
| | - Atsushi Hiraoka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime, 790-0024, Japan
| | - Fujimasa Tada
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, 880-2 Yamanishicho, Matsuyama, Ehime, 791-8026, Japan
| | - Hironori Ochi
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime, 790-8524, Japan
| | - Yoshiyasu Kisaka
- Department of Gastroenterology, Uwajima City Hospital, 1-1 Gotenmachi, Uwajima, Ehime, 798-8510, Japan
| | - Seiji Nakanishi
- Department of Gastroenterology, Ehime Prefectural Imabari Hospital, 4-5-5 Ishiicho, Imabari, Ehime, 794-0006, Japan
| | - Sen Yagi
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, 880-2 Yamanishicho, Matsuyama, Ehime, 791-8026, Japan
| | - Kazuhiko Yamauchi
- Department of Gastroenterology, National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon, Ehime, 791-0203, Japan
| | - Makoto Higashino
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, 880-2 Yamanishicho, Matsuyama, Ehime, 791-8026, Japan
| | - Kana Hirooka
- Department of Gastroenterology, National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon, Ehime, 791-0203, Japan
| | - Makoto Morita
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yuki Okazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
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13
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Kawagishi N, Suda G, Yamamoto Y, Baba M, Furuya K, Maehara O, Ohnishi S, Yoshida S, Fu Q, Yang Z, Hosoda S, Tokuchi Y, Kitagataya T, Ohara M, Suzuki K, Nakai M, Sho T, Natsuizaka M, Ogawa K, Sakamoto N. Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C. Viruses 2023; 15:181. [PMID: 36680221 PMCID: PMC9862289 DOI: 10.3390/v15010181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/03/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014-2020 were screened and evaluated for HCC occurrence or recurrence every three-six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34-6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18-6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs.
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Affiliation(s)
- Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Yoshiya Yamamoto
- Department of Gastroenterology, Hakodate Municipal Hospital, Sapporo 0608638, Japan
| | - Masaru Baba
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Sapporo 0608638, Japan
| | - Ken Furuya
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Sapporo 0608638, Japan
| | - Osamu Maehara
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 0608638, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 0608638, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Qingjie Fu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Zijian Yang
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 0608638, Japan
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14
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Kozuka R, Tamori A, Enomoto M, Muto-Yukawa Y, Odagiri N, Kotani K, Motoyama H, Kawamura E, Hagihara A, Fujii H, Uchida-Kobayashi S, Kawada N. Risk factors for liver-related and non-liver-related mortality following a sustained virological response after direct-acting antiviral treatment for hepatitis C virus infection in a real-world cohort. J Viral Hepat 2022; 30:374-385. [PMID: 36583600 DOI: 10.1111/jvh.13795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/15/2022] [Accepted: 12/17/2022] [Indexed: 12/31/2022]
Abstract
A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84-2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m2 (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m2 at baseline (p = .012; HR, 3.407) and albumin-bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.
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Affiliation(s)
- Ritsuzo Kozuka
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Akihiro Tamori
- Department of Hepatology, Kashiwara Municipal Hospital, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Yoshimi Muto-Yukawa
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Naoshi Odagiri
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kohei Kotani
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Sawako Uchida-Kobayashi
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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15
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Tahata Y, Sakamori R, Yamada R, Kodama T, Hikita H, Nozaki Y, Oshita M, Hiramatsu N, Miyazaki M, Mita E, Yamamoto K, Ohkawa K, Kaneko A, Ito T, Doi Y, Yakushijin T, Hijioka T, Fukui H, Imanaka K, Yoshida Y, Yamada Y, Tatsumi T, Takehara T. Risk of hepatocellular carcinoma after sustained virologic response in hepatitis C virus patients without advanced liver fibrosis. Hepatol Res 2022; 52:824-832. [PMID: 35749289 DOI: 10.1111/hepr.13806] [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: 05/09/2022] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 12/24/2022]
Abstract
AIM Hepatocellular carcinoma (HCC) after sustained virologic response (SVR) has been observed even in hepatitis C virus (HCV) patients without advanced liver fibrosis. Identifying predictors for HCC incidence in patients without advanced liver fibrosis will enable efficient post-SVR HCC surveillance. This study aimed to develop a scoring system to predict the incidence of HCC after SVR in HCV patients without advanced liver fibrosis. METHODS A total of 1682 HCV patients without advanced liver fibrosis (defined as Fibrosis-4 index <3.25) with no history of HCC who initiated direct-acting antiviral treatment between September 2014 and October 2020 at 26 institutions, and achieved SVR24, were included. We divided 1682 patients into training (1122) and validation (560) cohorts. RESULTS In the multivariate analysis, baseline age ≥ 65 years (p = 0.030), alanine aminotransferase (ALT) levels at SVR24 ≥ 30 U/l (p = 0.001), and α-fetoprotein (AFP) levels at SVR24 ≥ 5.0 ng/ml (p = 0.001) were independent predictors for HCC incidence in the training cohort. We developed a scoring system to predict HCC incidence after SVR24 using these three factors (1 point was added for each factor). The cumulative HCC incidence rates at 5 years were 7.1% in patients who scored 2 or 3, and no patients developed HCC in those who scored 0 in the validation cohort. CONCLUSIONS Our scoring system using the three factors of baseline age, ALT levels at SVR, and AFP levels at SVR is useful for post-SVR HCC surveillance of patients without advanced liver fibrosis.
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Affiliation(s)
- Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | | | | | | | - Eiji Mita
- National Hospital Organization Osaka Medical Center, Osaka, Japan
| | - Keiji Yamamoto
- National Hospital Organization Minami Wakayama Medical Center, Tanabe, Japan
| | | | | | - Toshifumi Ito
- Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan
| | | | | | - Taizo Hijioka
- National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Japan
| | | | | | | | | | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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16
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Shiha G, Soliman R, Mikhail NNH, Carrat F, Azzi J, Nathalie GC, Toyoda H, Uojima H, Nozaki A, Takaguchi K, Hiraoka A, Atsukawa M, Abe H, Matsuura K, Mikami S, Watanabe T, Tsuji K, Ishikawa T, Suri V, Osinusi A, Ni L, Zou J, Sarin SK, Kumar M, Jalal PK, Hashim MA, Hassan M, Lopez SA, Bañares R, Ahumada AM, Mousa NH, Eslam M, Waked I. International multicenter validation of GES score for HCC risk stratification in chronic hepatitis C patients. J Viral Hepat 2022; 29:807-816. [PMID: 35657138 DOI: 10.1111/jvh.13717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/15/2022] [Accepted: 04/03/2022] [Indexed: 12/28/2022]
Abstract
We have recently demonstrated the ability of a simple predictive model (GES) score to determine the risk of hepatocellular carcinoma (HCC) after using direct-acting antivirals. However, our results were restricted to Egyptian patients with hepatitis C virus (HCV) genotype 4. Therefore, we studied a large, independent cohort of multiethnic populations through our international collaborative activity. Depending on their GES scores, patients are stratified into low risk (≤ 6/12.5), intermediate risk (> 6-7.5/12.5), and high risk (> 7.5/12.5) for HCC. A total of 12,038 patients with chronic HCV were analyzed in this study, of whom 11,202 were recruited from 54 centers in France, Japan, India, the U.S., and Spain, and the remaining 836 were selected from the Gilead-sponsored randomized controlled trial conducted across the U.S., Europe, Canada, and Australia. Descriptive statistics and log-rank tests. The performance of the GES score was evaluated using Harrell's C-index (HCI). The GES score proved successful at stratifying all patients into 3 risk groups, namely low-risk, intermediate-risk, and high-risk. It also displayed significant predictive value for HCC development in all participants (p < .0001), with HCI ranging from 0.55 to 0.76 among all cohorts after adjusting for HCV genotypes and patient ethnicities. The GES score can be used to stratify HCV patients into 3 categories of risk for HCC, namely low-risk, intermediate-risk, and high-risk, irrespective of their ethnicities or HCV genotypes. This international multicenter validation may allow the use of GES score in individualized HCC risk-based surveillance programs.
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Affiliation(s)
- Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), El Mansoura, Egypt
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), El Mansoura, Egypt
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Fuad, Egypt
| | - Nabiel N H Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), El Mansoura, Egypt
- Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Asyut, Egypt
| | - Fabrice Carrat
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
- AP-HP, Sorbonne Université, Hôpital Saint-Antoine, Santé Publique, Paris, France
| | - Jessica Azzi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | - Ganne-Carrié Nathalie
- APHP, Liver Unit, AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, Bobigny, France
- Université Sorbonne Paris Nord, Bobigny, France
- Inserm, UMR-1138 « Functional Genomics of solid tumors », Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akito Nozaki
- Gastroenterology Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Abe
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatusdo Central General Hospital, Matsudo, Japan
| | - Kentaro Matsuura
- Department of Virology & Liver Unit, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Noda, Japan
| | - Tsunamasa Watanabe
- Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kunihiko Tsuji
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Hepatology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Vithika Suri
- Gilead Sciences, Inc, Foster City, California, USA
| | - Anu Osinusi
- Gilead Sciences, Inc, Foster City, California, USA
| | - Liyun Ni
- Gilead Sciences, Inc, Foster City, California, USA
| | - Jun Zou
- Gilead Sciences, Inc, Foster City, California, USA
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Prasun Kumar Jalal
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA
| | - Mahmoud A Hashim
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA
| | - Manal Hassan
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA
- Department of Epidemiology, Division of Cancer Prevention and Population Sciences, MD Anderson, Houston, Texas, USA
| | - Sonia Alonso Lopez
- Liver Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain
- Instituto De Investigación SanitariaGregorio Marañón (IiSGM), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Rafael Bañares
- Liver Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain
- Instituto De Investigación SanitariaGregorio Marañón (IiSGM), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Adriana M Ahumada
- Liver Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain
| | - Nasser Hamed Mousa
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| | - Imam Waked
- Hepatology Department, National Liver Institute, Menoufia University, Shebeen El-Kom, Egypt
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17
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Tada T, Kurosaki M, Tamaki N, Yasui Y, Mori N, Tsuji K, Hasebe C, Joko K, Akahane T, Furuta K, Kobashi H, Fujii H, Ishii T, Marusawa H, Kondo M, Kojima Y, Yoshida H, Uchida Y, Nakamura S, Izumi N. General evaluation score
for predicting the development of
hepatocellular carcinoma
in patients with advanced liver fibrosis associated with
hepatitis C virus
genotype 1 or 2 after
direct‐acting antiviral
therapy. JGH Open 2022; 6:487-495. [PMID: 35822118 PMCID: PMC9260214 DOI: 10.1002/jgh3.12778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/05/2022] [Accepted: 05/24/2022] [Indexed: 11/28/2022]
Abstract
Background and Aim To validate a composite predictive model for hepatocellular carcinoma (HCC) development in patients with advanced liver fibrosis associated with chronic hepatitis C virus (HCV) who have received direct‐acting antiviral (DAA) therapy and achieved sustained virologic response (SVR). Methods This study included 1258 patients with advanced liver fibrosis associated with HCV genotype 1, 2, or both. General evaluation score (GES), which is based on sex, age, fibrosis stage, albumin, and α‐fetoprotein, was used as a composite predictive model. Results There were 645 (51.3%) patients in the low‐risk group, 228 (18.1%) in the intermediate‐risk group, and 385 (30.6%) in the high‐risk group based on GES categories. The 12‐, 36‐, and 60‐month cumulative incidence of HCC was 0.7%, 5.3%, and 13.0%, respectively. Multivariable analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 1.863; 95% confidence interval [CI], 1.204–2.883), F4 fibrosis stage (HR, 3.199; 95% CI, 1.696–6.036), and albumin (HR, 0.489; 95% CI, 0.288–0.828) are independently associated with HCC development. The incidence of HCC differed significantly by GES‐based risk category (P < 0.001). Cox proportional hazards models showed that, with the low‐risk group as the referent, the HR for HCC development was 1.875 (95% CI, 1.000–3.514) in the intermediate‐risk group and 2.819 (95% CI, 1.716–4.630) in the high‐risk group. GES had better predictive ability for HCC development than fibrosis‐4 index according to time‐dependent receiver operating characteristic analysis. Conclusion GES is useful for predicting HCC development in patients with advanced liver fibrosis after SVR.
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Affiliation(s)
- Toshifumi Tada
- Department of Internal Medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
| | - Nami Mori
- Department of Gastroenterology Hiroshima Red Cross Hospital and Atomic‐Bomb Survivors Hospital Hiroshima Japan
| | - Keiji Tsuji
- Department of Gastroenterology Hiroshima Red Cross Hospital and Atomic‐Bomb Survivors Hospital Hiroshima Japan
| | - Chitomi Hasebe
- Department of Gastroenterology Japanese Red Cross Asahikawa Hospital Asahikawa Japan
| | - Koji Joko
- Center for Liver‐Biliary‐Pancreatic Disease Matsuyama Red Cross Hospital Matsuyama Japan
| | - Takehiro Akahane
- Department of Gastroenterology Japanese Red Cross Ishinomaki Hospital Ishinomaki Japan
| | - Koichiro Furuta
- Department of Gastroenterology Masuda Red Cross Hospital Masuda Japan
| | - Haruhiko Kobashi
- Department of Gastroenterology Japanese Red Cross Okayama Hospital Okayama Japan
| | - Hideki Fujii
- Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Kyoto Japan
| | - Toru Ishii
- Department of Gastroenterology Japanese Red Cross Akita Hospital Akita Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology Japanese Red Cross Osaka Hospital Osaka Japan
| | - Masahiko Kondo
- Department of Gastroenterology Japanese Red Cross Otsu Hospital Otsu Shiga Japan
| | - Yuji Kojima
- Department of Hepatology Japanese Red Cross Ise Hospital Ise Japan
| | - Hideo Yoshida
- Department of Gastroenterology Japanese Red Cross Medical Center Tokyo Japan
| | - Yasushi Uchida
- Department of Gastroenterology Japanese Red Cross Matsue Hospital Matsue Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
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18
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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19
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Tada T, Kumada T, Matono T, Nakamura S, Sue M, Matsuo Y, Takatani M, Iijima H, Tanaka J. Characteristics of hepatocellular carcinoma in patients with hepatitis C virus who received direct‐acting antiviral therapy and achieved sustained virological response: The impact of a hepatologist on surveillance. JGH Open 2022; 6:462-469. [PMID: 35822120 PMCID: PMC9260217 DOI: 10.1002/jgh3.12774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/08/2022] [Accepted: 05/14/2022] [Indexed: 11/28/2022]
Abstract
Background and Aim The relationship between the characteristics of hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) with direct‐acting antiviral (DAA) therapy and surveillance status has not been sufficiently investigated. This study investigated the clinical risk factors for HCC development and HCC characteristics according to which type of physician performed follow‐up after SVR. Methods A total of 1070 patients in whom hepatitis C virus (HCV) was eradicated with DAA therapy were evaluated. Results There were 458 patients followed by hepatologists (specialist group) and 612 followed by non‐hepatologists (non‐specialist group) after SVR. During the follow‐up period, 54 patients developed HCC. The 1‐, 2‐, 3‐, 4‐, and 5‐year cumulative incidence rates of HCC were 1.8, 4.1, 6.9, 10.5, and 17.2%, respectively. Multivariate Cox proportional hazards analysis showed that male sex (hazard ratio [HR], 3.139; 95% confidence interval [CI], 1.732–5.690), α‐fetoprotein level (HR, 1.056; 95% CI, 1.035–1.077), and fibrosis‐4 (FIB‐4) index (HR, 1.051; 95% CI, 1.017–1.085) were significantly associated with HCC development, while the follow‐up physician type after SVR was not. There were 25 patients with stage I HCC, 17 with stage II, 9 with stage III, and 3 with stage IV. Multivariate ordinal logistic regression showed that follow‐up physician type (non‐specialist) (HR, 39.100; 95% CI, 9.350–224.00) was independently associated with HCC stage, while α‐fetoprotein level and FIB‐4 index were not. Conclusion When patients have more risk factors for HCC development after SVR (i.e., male sex, elevated α‐fetoprotein, or elevated FIB‐4 index), they should be followed by a hepatologist for HCC surveillance.
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Affiliation(s)
- Toshifumi Tada
- Department of Internal medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Hyogo Medical University Nishinomiya Japan
| | | | - Tomomitsu Matono
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Hyogo Medical University Nishinomiya Japan
- Department of Internal medicine Himeji St. Mary's Hospital Himeji Japan
| | - Shinichiro Nakamura
- Department of Internal medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Masahiko Sue
- Department of Internal medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Yu Matsuo
- Department of Internal medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Masahiro Takatani
- Department of Internal medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Hiroko Iijima
- Department of Internal Medicine, Division of Gastroenterology and Hepatology Hyogo Medical University Nishinomiya Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan
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20
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Azzi J, Dorival C, Cagnot C, Fontaine H, Lusivika-Nzinga C, Leroy V, De Ledinghen V, Tran A, Zoulim F, Alric L, Gournay J, Bronowicki JP, Decaens T, Riachi G, Mikhail N, Soliman R, Shiha G, Pol S, Carrat F, Ganne-Carrié N. Prediction of hepatocellular carcinoma in Hepatitis C patients with advanced fibrosis after sustained virologic response. Clin Res Hepatol Gastroenterol 2022; 46:101923. [PMID: 35405354 DOI: 10.1016/j.clinre.2022.101923] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/07/2022] [Accepted: 04/05/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS Prediction of hepatocellular carcinoma (HCC) occurrence in patients with chronic hepatitis C (HCV) who achieved a sustained virological response (SVR) after direct acting antivirals (DAAs) remains challenging. METHODS Among HCC-free HCV patients with advanced fibrosis enrolled in the ANRS CO22 HEPATHER cohort who achieved SVR 12 weeks after treatment with DAAs, HCC predictive models were developed using Cox multivariable regression. The derived score was externally validated in a large Egyptian cohort. Our main outcome was the HCC-free survival. RESULTS During follow-up (median 3.05 years), 153 out of 3531 patients developed a HCC. Main variables associated with HCC occurrence were: male gender, HCV genotype 3, esophageal varices, albumin < 40 g/L, total bilirubin >11 µmol/L and hypercholesterolemia before DAA initiation, together with age > 58 years, FIB-4 index ≥3.25 evaluated at SVR. A score was established allowing the stratification of patients by high (score ≥ 12/22), intermediate (7 ≤ score <12) and low risk of HCC (score < 7/22) with 3-yrs HCC incidence of 18.96%, 5.50% and 1.65%, respectively. The integrated time-dependent area under the ROC curve (i-AUC) was 0.76 in our patients and 0.61 in the validation cohort. CONCLUSION The externally validated HEPATHER HCC score has good short-term predictive performance in HCV- patients who achieved SVR12 after DAAs allowing to identify high-risk patients in whom HCC screening may be cost-effective and low-risk patients in whom HCC screening may be superfluous in the first 3 years after SVR.
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Affiliation(s)
- Jessica Azzi
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Céline Dorival
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Carole Cagnot
- ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), Unit for Basic and Clinical Research on Viral Hepatitis, Paris, France
| | | | - Clovis Lusivika-Nzinga
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Vincent Leroy
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - Victor De Ledinghen
- Hepatology Unit Hôpital Haut-Lévêque, Pessac, INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | - Albert Tran
- Université Côte d'Azur, Nice, France; CHU de Nice, Digestive Center, Nice, France; INSERM, U1065, C3M, Team 8 « Chronic liver diseases associated with obesity and alcohol », Nice, France
| | - Fabien Zoulim
- Department of Hepatology, Hospices Civils de Lyon, INSERM U1052, Université de Lyon, Lyon, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, France
| | - Jérôme Gournay
- Gastroenterology and Hepatology Department, Institut des Maladies de l'Appareil Digestif, University Hospital of Nantes, Nantes, France
| | - Jean-Pierre Bronowicki
- Inserm U1254 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Thomas Decaens
- Department of Hepatology and Gastroenterology, CHU Grenoble-Alpes, Université Grenoble-Alpes, Institute for Advanced Biosciences INSERM U1209, Grenoble, France
| | - Ghassan Riachi
- Department of Hepatology and Gastroenterology, CHU Charles Nicolle, Rouen, France
| | - Nabiel Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt; Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Assuit, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt; Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt; Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Stanislas Pol
- AP-HP, Hôpital Cochin, Unité d'Hépatologie, Paris, France; Université de Paris, INSERM U1223 and USM-20, Institut Pasteur, Paris, France
| | - Fabrice Carrat
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; AP-HP, Sorbonne Université, Hôpital Saint-Antoine, Santé Publique, Paris, France
| | - Nathalie Ganne-Carrié
- AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, APHP, Liver Unit, Bobigny, France; Université Sorbonne Paris Nord, Bobigny, France; Inserm, UMR-1138 « Functional Genomics of solid tumors », Centre de Recherche des Cordeliers, Université de Paris, France.
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21
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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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22
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Mawatari S, Kumagai K, Oda K, Tabu K, Ijuin S, Fujisaki K, Tashima S, Inada Y, Uto H, Saisyoji A, Hiramine Y, Hashiguchi M, Tamai T, Hori T, Taniyama O, Toyodome A, Sakae H, Kure T, Sakurai K, Moriuchi A, Kanmura S, Ido A. Features of patients who developed hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C Virus. PLoS One 2022; 17:e0262267. [PMID: 35020772 PMCID: PMC8754290 DOI: 10.1371/journal.pone.0262267] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/21/2021] [Indexed: 02/07/2023] Open
Abstract
Background The features of hepatitis C virus patients with a sustained virologic response (SVR) who developed hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) therapy are unclear. Methods The study population included 1494 DAA-SVR patients without a history of HCC. The cumulative carcinogenesis rate after the end of treatment (EOT) and factors related to HCC were analyzed. Results Sixty (4.0%) patients developed HCC during a median observation period of 47.6 months. At four years, the cumulative carcinogenesis rate was 4.7%. A Cox proportional hazards analysis showed that age ≥73 years (hazard ratio [HR]: 2.148), male sex (HR: 3.060), hyaluronic acid (HA) ≥75 ng/mL (HR: 3.996), alpha-fetoprotein at EOT (EOT-AFP) ≥5.3 ng/mL (HR: 4.773), and albumin at EOT (EOT-Alb) <3.9 g/dL (HR: 2.305) were associated with HCC development. Especially, EOT-AFP ≥5.3 ng/mL was associated with HCC development after 3 years from EOT (HR: 6.237). Among patients who developed HCC, AFP did not increase in patients with EOT-AFP <5.3 ng/mL at the onset of HCC. Of these 5 factors, EOT-AFP ≥5.3 ng/mL was scored as 2 points; the others were scored as 1 point. The 4-year cumulative carcinogenesis rate for patients with total scores of 0–2, 3–4, and 5–6 points were 0.6%, 11.9%, and 27.1%, respectively (p<0.001). Conclusions EOT-AFP ≥5.3 ng/mL is useful for predicting HCC development after an SVR. However, AFP does not increase in patients with EOT-AFP <5.3 ng/mL at the onset of HCC. The combination of EOT-AFP, age, sex, HA, and EOT-Alb is important for predicting carcinogenesis.
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Affiliation(s)
- Seiichi Mawatari
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- * E-mail:
| | - Kotaro Kumagai
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kohei Oda
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kazuaki Tabu
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Sho Ijuin
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kunio Fujisaki
- Department of Hepatology, Kirishima Medical Center, Hayato-cho, Kirishima, Kagoshima, Japan
| | - Shuzo Tashima
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Hepatology, Kirishima Medical Center, Hayato-cho, Kirishima, Kagoshima, Japan
| | - Yukiko Inada
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, Miyazaki, Japan
| | - Hirofumi Uto
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, Miyazaki, Japan
| | - Akiko Saisyoji
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Yasunari Hiramine
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Masafumi Hashiguchi
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Kagoshima, Japan
| | - Tsutomu Tamai
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Kagoshima, Japan
| | - Takeshi Hori
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, Kagoshima, Japan
| | - Ohki Taniyama
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Ai Toyodome
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Haruka Sakae
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takeshi Kure
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Gastroenterology, Kagoshima Medical Association Hospital, Kagoshima, Japan
| | - Kazuhiro Sakurai
- Department of Gastroenterology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
| | - Akihiro Moriuchi
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Gastroenterology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
| | - Shuji Kanmura
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Akio Ido
- Department of Human and Environmental Sciences, Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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23
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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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24
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Shiha G, Mikhail NNH, Soliman R, Hassan A, Eslam M. Predictive performance and clinical utility of HCC risk scores in chronic hepatitis C: a comparative study. Hepatol Int 2022; 16:159-170. [PMID: 35034266 DOI: 10.1007/s12072-021-10284-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Many HCC risk prediction scores were developed to guide HCC risk stratification and identify CHC patients who either need intensified surveillance or may not require screening. There is a need to compare different scores and their predictive performance in clinical practice. We aim to compare the newest HCC risk scores evaluating their discriminative ability, and clinical utility in a large cohort of CHC patients. PATIENTS AND METHODS The performance of the scores was evaluated in 3075 CHC patients who achieved SVR following DAAs using Log rank, Harrell's c statistic, also tested for HCC-risk stratification and negative predictive values. RESULTS HCC developed in 212 patients within 5 years follow-up. Twelve HCC risk scores were identified and displayed significant Log rank (p ≤ 0.05) except Alonso-Lopez TE-HCC, and Chun scores (p = 0.374, p = 0.053, respectively). Analysis of the remaining ten scores revealed that ADRES, GES pre-post treatment, GES algorithm and Watanabe (post-treatment) scores including dynamics of AFP, were clinically applicable and demonstrated good statistical performance; Log rank analysis < 0.001, Harrell's C statistic (0.66-0.83) and high negative predictive values (94.38-97.65%). In these three scores, the 5 years cumulative IR in low risk groups be very low (0.54-1.6), so screening could be avoided safely in these patients. CONCLUSION ADRES, GES (pre- and post-treatment), GES algorithm and Watanabe (post-treatment) scores seem to offer acceptable HCC-risk predictability and clinical utility in CHC patients. The dynamics of AFP as a component of these scores may explain their high performance when compared to other scores.
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Affiliation(s)
- Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt.
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Nabiel N H Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt
- Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Ayman Hassan
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
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25
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Nakai M, Yamamoto Y, Baba M, Suda G, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Sho T, Morikawa K, Ogawa K, Furuya K, Sakamoto N. Prediction of hepatocellular carcinoma using age and liver stiffness on transient elastography after hepatitis C virus eradication. Sci Rep 2022; 12:1449. [PMID: 35087141 PMCID: PMC8795443 DOI: 10.1038/s41598-022-05492-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Liver stiffness measurement (LSM) is a useful tool for assessing advanced liver fibrosis, an important risk factor for hepatocellular carcinoma (HCC) following hepatitis C (HCV) eradication. This study aimed to clarify the non-invasive factors associated with HCC following sustained virological response (SVR) and to identify the low-risk group. 567 patients without history of HCC who achieved SVR at 24 weeks (SVR24) after IFN-free treatment were retrospectively analyzed. The cumulative incidence of HCC and the risk factors were examined using pre-treatment and SVR24 data. The median observation period was 50.2 months. Thirty cases of HCC were observed, and the 4-year cumulative incidence of HCC was 5.9%. In multivariate analysis, significant pre-treatment factors were age ≥ 71 years (hazard ratio [HR]: 3.402) and LSM ≥ 9.2 kPa (HR: 6.328); SVR24 factors were age ≥ 71 years (HR: 2.689) and LSM ≥ 8.4 kPa (HR: 6.642). In cases with age < 71 years and LSM < 8.4 kPa at the time of SVR24, the 4-year cumulative incidence of HCC was as low as 1.1%. Both pre-treatment LSM (≥ 9.2 kPa) and SVR24 LSM (≥ 8.4 kPa) and age (≥ 71 years) are useful in predicting the risk of HCC after SVR with IFN-free treatment. Identification of low-risk individuals may improve the efficiency of follow-up.
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Affiliation(s)
- Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yoshiya Yamamoto
- Department of Gastroenterology, Hakodate Municipal Hospital, Hakodate, Hokkaido, Japan
| | - Masaru Baba
- Department of Gastroenterology, JCHO Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology, Hakodate Municipal Hospital, Hakodate, Hokkaido, Japan
| | - Akihisa Nakamura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Ken Furuya
- Department of Gastroenterology, JCHO Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
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26
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Tada T, Kurosaki M, Tamaki N, Yasui Y, Mori N, Tsuji K, Hasebe C, Joko K, Akahane T, Furuta K, Kobashi H, Kimura H, Yagisawa H, Marusawa H, Kondo M, Kojima Y, Yoshida H, Uchida Y, Nakamura S, Izumi N. A validation study of after direct-acting antivirals recommendation for surveillance score for the development of hepatocellular carcinoma in patients with hepatitis C virus infection who had received direct-acting antiviral therapy and achieved sustained virological response. JGH Open 2022; 6:20-28. [PMID: 35071784 PMCID: PMC8762616 DOI: 10.1002/jgh3.12690] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/25/2021] [Accepted: 11/28/2021] [Indexed: 12/19/2022]
Abstract
Background and Aim The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with hepatitis C virus (HCV) who have received direct-acting antiviral (DAA) therapy and achieved sustained virological response (SVR). This study validated a composite predictive model for HCC in these patients. Methods This study included 3058 patients in whom HCV was eradicated with DAA therapy. After DAAs recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used as a composite predictive model for HCC development. Results The 1-, 3-, and 5-year cumulative incidence rates of HCC were 0.9, 4.5, and 15.2%, respectively. Multivariate analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 2.646; 95% confidence interval [CI], 1.790-3.911), FIB-4 index >3.25 (HR, 2.891; 95% CI, 1.947-4.293), and α-fetoprotein >5 ng/mL (HR, 2.835; 95% CI, 1.914-4.200) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES score (P < 0.001). Cox proportional hazards models showed that compared to the ADRES score 0 group, the HR for HCC development was 2.947 (95% CI, 1.367-6.354) in the ADRES score 1 group, 9.171 (95% CI, 4.339-19.380) in the ADRES score 2 group, and 20.630 (95% CI, 8.641-49.230) in the ADRES score 3 group. ADRES score had superior predictive power for HCC development compared with the FIB-4 index and α-fetoprotein according to time-dependent receiver operating characteristic analysis. Conclusion The ADRES score is useful for predicting HCC development after SVR.
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Affiliation(s)
- Toshifumi Tada
- Department of Internal Medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
| | - Nami Mori
- Department of Gastroenterology Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital Hiroshima Hiroshima Japan
| | - Keiji Tsuji
- Department of Gastroenterology Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital Hiroshima Hiroshima Japan
| | - Chitomi Hasebe
- Department of Gastroenterology Japanese Red Cross Asahikawa Hospital Asahikawa Hokkaido Japan
| | - Koji Joko
- Center for Liver-Biliary-Pancreatic Disease Matsuyama Red Cross Hospital Matsuyama Ehime Japan
| | - Takehiro Akahane
- Department of Gastroenterology Japanese Red Cross Ishinomaki Hospital Ishinomaki Miyagi Japan
| | - Koichiro Furuta
- Department of Gastroenterology Masuda Red Cross Hospital Masuda Shimane Japan
| | - Haruhiko Kobashi
- Department of Gastroenterology Japanese Red Cross Okayama Hospital Okayama Okayama Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Kyoto Japan
| | - Hitoshi Yagisawa
- Department of Gastroenterology Japanese Red Cross Akita Hospital Akita Akita Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology Japanese Red Cross Osaka Hospital Osaka Japan
| | - Masahiko Kondo
- Department of Gastroenterology Japanese Red Cross Otsu Hospital Otsu Shiga Japan
| | - Yuji Kojima
- Department of Hepatology Japanese Red Cross Ise Hospital Ise Mie Japan
| | - Hideo Yoshida
- Department of Gastroenterology Japanese Red Cross Medical Center Tokyo Japan
| | - Yasushi Uchida
- Department of Gastroenterology Japanese Red Cross Matsue Hospital Matsue Shimane Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine Japanese Red Cross Society Himeji Hospital Himeji Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Tokyo Japan
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27
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Kuwano A, Yada M, Nagasawa S, Tanaka K, Morita Y, Masumoto A, Motomura K. Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment. J Viral Hepat 2022; 29:35-42. [PMID: 34661320 DOI: 10.1111/jvh.13625] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/14/2021] [Accepted: 09/21/2021] [Indexed: 01/15/2023]
Abstract
Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1 year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1 year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5 years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8 ng/ml ≥1 year following treatment with DAAs (HR, 9.7; p < .0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1 year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan.,Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | | | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Yusuke Morita
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Akihide Masumoto
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka, Japan
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28
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Tahata Y, Sakamori R, Yamada R, Kodama T, Hikita H, Hagiwara H, Imai Y, Hiramatsu N, Tamura S, Yamamoto K, Oshita M, Ohkawa K, Hijioka T, Fukui H, Ito T, Doi Y, Yamada Y, Yakushijin T, Yoshida Y, Tatsumi T, Takehara T. Letter: evaluation and proposed reclassification of HCC prediction model of Tahata et al. in chronic hepatitis C genotype 4 patient. Authors' reply. Aliment Pharmacol Ther 2022; 55:258-259. [PMID: 34970764 DOI: 10.1111/apt.16721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | | | | | | | - Keiji Yamamoto
- National Hospital Organization Minami Wakayama Medical Centre, Tanabe, Japan
| | | | | | - Taizo Hijioka
- National Hospital Organization Osaka Minami Medical Centre, Kawachinagano, Japan
| | | | - Toshifumi Ito
- Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan
| | | | | | | | | | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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29
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Miyasaka A, Yoshida Y, Suzuki A, Sawara K, Takikawa Y. A Novel Standard for Hepatocellular Carcinoma Screening Intensity After Hepatitis C Elimination. Int J Gen Med 2021; 14:8935-8943. [PMID: 34866934 PMCID: PMC8636695 DOI: 10.2147/ijgm.s344492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/12/2021] [Indexed: 12/22/2022] Open
Abstract
Purpose To investigate long-term incidence of hepatocellular carcinoma (HCC) and the factors associated with HCC occurrence after achieving sustained virological response (SVR) by direct-acting antiviral agent (DAA) treatment for hepatitis C virus (HCV). Methods A total of 476 patients (male 227, female 249; median age 68) with chronic HCV infection who were treated with DAAs and achieved SVR were analyzed. The incidence of HCC and factors related to the development of HCC after HCV elimination were evaluated. Results The median observation period was 46.4 months. During this period, 40 patients developed HCC. The incidence rates of HCC were 3.7%, 6.0%, 7.1%, 9.3%, and 10.6% at 1, 2, 3, 4, and 5 years post-SVR12, respectively. Multivariate analysis with pre-treatment factors revealed that platelet count, α-fetoprotein, fibrosis-4 (Fib-4) index, and previous HCC history were independent factors that contributed to development of HCC post-SVR following DAA treatment. Of these factors, previous HCC history was the most significant, followed by Fib-4 index. Using these two factors, a novel scoring system was established. The presence of previous HCC history was scored as 2, and then, the absence of previous HCC history was stratified by Fib-4 index (≥3.07, 1; <3.07, 0). The HCC occurrence rate at 5 years was 0.4% in the 0-point group, 6.8% in the 1-point group, and 55.6% in the 2-point group, respectively. Conclusion Fib-4 index and previous HCC history were independent predictors for development of HCC after DAA treatment. Patients with these risk factors require careful observation.
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Affiliation(s)
- Akio Miyasaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Shiwa-gun, Iwate, Japan.,Department of Gastroenterology, Iwate Prefectural Ninohe Hospital, Ninohe, Iwate, Japan
| | - Yuichi Yoshida
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Shiwa-gun, Iwate, Japan.,Department of Gastroenterology, Iwate Prefectural Ninohe Hospital, Ninohe, Iwate, Japan
| | - Akiko Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Shiwa-gun, Iwate, Japan
| | - Kei Sawara
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Shiwa-gun, Iwate, Japan.,Department of Gastroenterology, Iwate Prefectural Kamaishi Hospital, Kamaishi, Iwate, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Shiwa-gun, Iwate, Japan
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30
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Tahata Y, Sakamori R, Yamada R, Kodama T, Hikita H, Hagiwara H, Imai Y, Hiramatsu N, Tamura S, Yamamoto K, Oshita M, Ohkawa K, Hijioka T, Fukui H, Ito T, Doi Y, Yamada Y, Yakushijin T, Yoshida Y, Tatsumi T, Takehara T. Prediction model for hepatocellular carcinoma occurrence in patients with hepatitis C in the era of direct-acting anti-virals. Aliment Pharmacol Ther 2021; 54:1340-1349. [PMID: 34618934 DOI: 10.1111/apt.16632] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/24/2021] [Accepted: 09/23/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Several factors associated with hepatocellular carcinoma (HCC) occurrence after sustained virological response (SVR) in patients with hepatitis C have been reported. However, few validation studies have been performed in the era of direct-acting anti-virals (DAAs). AIMS To develop a prediction model for HCC occurrence after DAA-mediated SVR and validate its usefulness. METHODS We analysed 2209 patients with SVR and without a history of HCC who initiated DAA treatment at 24 Japanese hospitals. These patients were divided into a training set (1473 patients) and a validation set (736 patients). RESULTS In the training set, multivariate Cox proportional hazards analysis showed that the baseline BMI (≥25.0 kg/m2 , P = 0.024), baseline fibrosis-4 (FIB-4) index (≥3.25, P = 0.001), albumin level at SVR (<4.0 g/dL, P = 0.010) and alpha-foetoprotein level at SVR (≥5.0 ng/mL, P = 0.006) were significantly associated with HCC occurrence. We constructed a prediction model for HCC occurrence with these four factors (2 points were added for the FIB-4 index, and 1 point was added for each of the other three factors). Receiver operating characteristics curve analysis identified a score of 2 as the optimal cut-off value for the prediction model (divided into 0-1 and 2-5). In the validation set, the sensitivity and negative predictive value for HCC occurrence were 87.5% and 99.7%, respectively, at 2 years and 71.4% and 98.0%, respectively, at 3 years. CONCLUSION A prediction model combining these four factors contributes to an efficient surveillance strategy for HCC occurrence after DAA-mediated SVR.
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31
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Váncsa S, Németh D, Hegyi P, Szakács Z, Farkas Á, Kiss S, Hegyi PJ, Kanjo A, Sarlós P, Erőss B, Pár G. Diabetes Mellitus Increases the Risk of Hepatocellular Carcinoma After Direct-Acting Antiviral Therapy: Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:744512. [PMID: 34733865 PMCID: PMC8558240 DOI: 10.3389/fmed.2021.744512] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Hepatitis C virus (HCV)-infected patients treated with direct-acting antivirals (DAAs) are still at risk of developing hepatocellular carcinoma (HCC) after sustained virologic response (SVR). This study aimed to investigate the role of diabetes mellitus (DM) as a potential predictive risk factor in developing de novo HCC in HCV-infected patients after DAA treatment. Methods: This study was registered on PROSPERO under registration number CRD42021230457. We performed a systematic search in four medical databases from inception through November 3rd, 2020. Studies were eligible if they reported on HCV-infected patients treated with DAAs and compared the frequency of de novo HCC in patients with and without DM. We calculated pooled odds ratios, unadjusted (UHR), and adjusted hazard ratios (AHR) with 95% confidence intervals (CIs) in meta-analysis. Results: We included 30 articles in our systematic review and meta-analysis. DM proved to be a significant risk factor of HCC in DAA-treated HCV patients in unadjusted (UHR = 1.44, CI: 1.15-1.79) and adjusted analyses (AHR = 1.31, CI: 1.06-1.62). In the group of patients achieving SVR after DAA therapy, DM increased the risk of HCC in unadjusted (UHR = 1.3, CI: 1.09-1.51) analysis; however, in adjusted results, the risk was non-significant (AHR = 1.07, CI: 0.89-1.28). In patients with advanced liver fibrosis, DM was a risk factor for HCC in adjusted (AHR = 1.36, CI: 1.03-1.8), but not in unadjusted analysis (UHR = 1.11, CI: 0.8-1.42). Conclusions: DM is an independent risk factor of de novo HCC after DAA treatment in HCV-infected patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=230457, identifier: CRD42021230457.
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Affiliation(s)
- Szilárd Váncsa
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Dávid Németh
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Ádám Farkas
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Szabolcs Kiss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Péter Jenő Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Anna Kanjo
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Heim Pál National Pediatric Institute, Budapest, Hungary
| | - Patrícia Sarlós
- Department of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Gabriella Pár
- Department of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
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Yongpisarn T, Thimphitthaya C, Laoveeravat P, Wongjarupong N, Chaiteerakij R. Non-invasive tests for predicting liver outcomes in chronic hepatitis C patients: A systematic review and meta-analysis. World J Hepatol 2021; 13:949-968. [PMID: 34552701 PMCID: PMC8422917 DOI: 10.4254/wjh.v13.i8.949] [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: 03/25/2021] [Revised: 06/14/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis leads to liver-related events in patients with chronic hepatitis C (CHC) infection. Although non-invasive tests (NITs) are critical to early detection of the development of liver fibrosis, the prognostic role of NITs remains unclear due to the limited types of NITs and liver outcomes explored in previous studies.
AIM To determine the prognostic value of NITs for risk stratification in CHC patients.
METHODS The protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42019128176). The systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search was performed using MEDLINE and EMBASE databases under a timeframe from the inception of the databases through February 25, 2020. We restricted our search to CHC cohort studies reporting an association between liver fibrosis assessed by NITs and the development of hepatocellular carcinoma, decompensation, or mortality. Pooled hazard ratios (HR) and area under the receiver operating characteristic (AUROC) for each NIT were estimated using a random effects model. Subgroup analyses were performed for NITs assessed at pre-treatment or post-treatment with sustained virologic response (SVR), treatment with either pegylated interferon and ribavirin or direct acting antiviral, Eastern or Western countries, and different cutoff points.
RESULTS The present meta-analysis included 29 cohort studies, enrolling 69339 CHC patients. Fibrosis-4 (FIB-4) index, aspartate aminotransferase to platelet ratio (APRI) score, and liver stiffness measurement (LSM) were found to have hepatocellular carcinoma predictive potential with pooled adjusted HRs of 2.48 [95% confidence interval (CI): 1.91-3.23, I2 = 96%], 4.24 (95%CI: 2.15-8.38, I2 = 20%) and 7.90 (95%CI: 3.98-15.68, I2 = 52%) and AUROCs of 0.81 (95%CI: 0.73-0.89, I2 = 77%), 0.81 (95%CI: 0.75-0.87, I2 = 68%), and 0.79 (95%CI: 0.63-0.96, I2 = 90%), respectively. Pooled adjusted HR with a pre-treatment FIB-4 cutoff of 3.25 was 3.22 (95%CI: 2.32-4.47, I2 = 80%). Pooled adjusted HRs for post-treatment with SVR FIB-4, APRI, and LSM were 3.01 (95%CI: 0.32-28.61, I2 = 89%), 9.88 (95%CI: 2.21-44.17, I2 = 24%), and 6.33 (95%CI: 2.57-15.59, I2 = 17%), respectively. Pooled adjusted HRs for LSM in patients with SVR following direct acting antiviral therapy was 5.55 (95%CI: 1.47-21.02, I2 = 36%). Pooled AUROCs for post-treatment with SVR FIB-4 and LSM were 0.75 (95%CI: 0.55-0.95, I2 = 88%) and 0.84 (95%CI: 0.66-1.03, I2 = 88%), respectively. Additionally, FIB-4 and LSM were associated with overall mortality, with pooled adjusted HRs of 2.07 (95%CI: 1.49-2.88, I2 = 27%) and 4.04 (95%CI: 2.40-6.80, I2 = 63%), respectively.
CONCLUSION FIB-4, APRI, and LSM showed potential for risk stratification in CHC patients. Cutoff levels need further validation.
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Affiliation(s)
- Tanat Yongpisarn
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Bangkok 10330, Thailand
| | - Chanattha Thimphitthaya
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Bangkok 10330, Thailand
| | - Passisd Laoveeravat
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, KY 40536, United States
| | - Nicha Wongjarupong
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Llorens-Revull M, Costafreda MI, Rico A, Guerrero-Murillo M, Soria ME, Píriz-Ruzo S, Vargas-Accarino E, Gabriel-Medina P, Rodríguez-Frías F, Riveiro-Barciela M, Perales C, Quer J, Sauleda S, Esteban JI, Bes M. Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy. PLoS One 2021; 16:e0254243. [PMID: 34242330 PMCID: PMC8270431 DOI: 10.1371/journal.pone.0254243] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND & AIMS HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. METHODS We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. RESULTS We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. CONCLUSIONS Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA's therapies.
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Affiliation(s)
- Meritxell Llorens-Revull
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Maria Isabel Costafreda
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Angie Rico
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Mercedes Guerrero-Murillo
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Maria Eugenia Soria
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Sofía Píriz-Ruzo
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Elena Vargas-Accarino
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Pablo Gabriel-Medina
- Liver Pathology Laboratory, Biochemistry and Microbiology Unit, Vall d’Hebron Hospital Universitari (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- Liver Pathology Laboratory, Biochemistry and Microbiology Unit, Vall d’Hebron Hospital Universitari (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Clinical Biochemistry Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Celia Perales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Josep Quer
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Silvia Sauleda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Juan Ignacio Esteban
- Liver Diseases-Viral Hepatitis Laboratory, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Marta Bes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
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D’Ambrosio R, Degasperi E, Lampertico P. Predicting Hepatocellular Carcinoma Risk in Patients with Chronic HCV Infection and a Sustained Virological Response to Direct-Acting Antivirals. J Hepatocell Carcinoma 2021; 8:713-739. [PMID: 34235108 PMCID: PMC8254542 DOI: 10.2147/jhc.s292139] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 06/02/2021] [Indexed: 12/26/2022] Open
Abstract
Chronic infection with hepatitis C virus (HCV) may complicate with hepatocellular carcinoma (HCC), especially in patients with cirrhosis. Although the achievement of a sustained virological response (SVR) had been associated with a reduction in the risk of HCC already in the Interferon era, some concerns initially raised following the use of direct-acting antivirals (DAA), as their use was associated with increased risk of HCC development and aggressiveness. However, studies demonstrated that the risk of HCC was strongly influenced by pre-treatment fibrosis stage and, eventually, prior HCC history more than the type of antiviral therapy. According to published studies, rates of de-novo HCC ranged between 1.4% and 13.6% in patients with cirrhosis or advanced fibrosis vs 0.9% and 5.9% in those with chronic hepatitis C (CHC). Conversely, rates of recurrent HCC were higher, ranging between 3.2% and 49% in cirrhotics vs 0% and 40% in CHC patients. Most studies tried to identify predictors of HCC development, either de-novo or recurrent, and some authors were also able to build predictive scores for HCC risk stratification, which however still need prospective validation. Whereas some clinical features, such as age, gender, presence of comorbidities and fibrosis stage, may influence both de-novo and recurrent HCC, previous tumour burden before DAA seems to prevail over these features in recurrent HCC risk prediction.
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Affiliation(s)
- Roberta D’Ambrosio
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Elisabetta Degasperi
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
- CRC “A. M. and A. Migliavacca” Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Watanabe T, Tokumoto Y, Joko K, Michitaka K, Horiike N, Tanaka Y, Tada F, Kisaka Y, Nakanishi S, Yamauchi K, Ochi H, Hiraoka A, Yagi S, Yukimoto A, Hirooka M, Abe M, Hiasa Y. AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy. BMC Cancer 2021; 21:699. [PMID: 34126947 PMCID: PMC8201700 DOI: 10.1186/s12885-021-08401-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 05/24/2021] [Indexed: 01/05/2023] Open
Abstract
Background An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. Methods Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as ‘early recurrence’, and recurrence more than 1 year after as ‘late recurrence’. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. Results Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026–1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96–0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. Conclusion Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08401-7.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime, 790-8524, Japan
| | - Kojiro Michitaka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime, 790-0024, Japan
| | - Norio Horiike
- Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime, 799-1502, Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime, 790-0067, Japan
| | - Fujimasa Tada
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, 880-2 Yamanishicho, Matsuyama, Ehime, 791-8026, Japan
| | - Yoshiyasu Kisaka
- Department of Gastroenterology, Uwajima City Hospital, 1-1 Gotenmachi, Uwajima, Ehime, 798-8510, Japan
| | - Seiji Nakanishi
- Department of Gastroenterology, Ehime Prefectural Imabari Hospital, 4-5-5 Ishiicho, Imabari, Ehime, 794-0006, Japan
| | - Kazuhiko Yamauchi
- Department of Gastroenterology, National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon, Ehime, 791-0203, Japan
| | - Hironori Ochi
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime, 790-8524, Japan
| | - Atsushi Hiraoka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime, 790-0024, Japan
| | - Sen Yagi
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, 880-2 Yamanishicho, Matsuyama, Ehime, 791-8026, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
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Ohfuji S, Matsuura T, Tamori A, Kubo S, Sasaki S, Kondo K, Ito K, Fukushima W. Lifestyles Associated with Prognosis After Eradication of Hepatitis C Virus: A Prospective Cohort Study in Japan. Dig Dis Sci 2021; 66:2118-2128. [PMID: 32720018 DOI: 10.1007/s10620-020-06475-0] [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: 03/02/2020] [Accepted: 07/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma develops in some patients with hepatitis C virus (HCV), even after achieving sustained virological response (SVR). AIMS We examined factors associated with liver disease progression in a prospective cohort study of SVR patients. METHODS Participants were patients who had visited a hospital for clinical follow-up of chronic HCV infection in 2005 and had reached SVR as a result of subsequent antiviral treatment. Baseline information including lifestyle and dietary habits before SVR was collected in 2005 using self-administered questionnaires, and clinical information before SVR was collected from medical records in 2005. Study outcome was liver disease progression such as liver cirrhosis, hepatocellular carcinoma, and/or liver disease-related death after SVR. Proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals for each variable. RESULTS Of 180 SVR patients, 27 patients (15%) showed liver disease progression after SVR: 26 (14%) were diagnosed with liver cirrhosis, two (1%) with hepatocellular carcinoma, and/or one (0.6%) with liver-disease-related death. Besides older age at SVR (HR = 11.9, P < 0.01) and aspartate aminotransferase-to-platelet ratio index score ≥ 1.0 before SVR (HR = 2.63, P = 0.03), alcohol drinkers before SVR (HR = 2.82, P = 0.06) were suggested to be associated with liver disease progression after SVR, whereas higher consumption of vitamin B12 before SVR showed a decreased HR for liver disease progression (HR = 0.41, P = 0.09). CONCLUSIONS Alcohol drinking might be associated with liver disease progression, whereas vitamin B12 intake might have protective effects against liver disease progression after eradication of HCV. Further studies are needed to confirm these findings.
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Affiliation(s)
- Satoko Ohfuji
- Department of Public Health, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan.
| | - Tomoka Matsuura
- Department of Public Health, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, Japan
| | - Satoshi Sasaki
- Department of Social and Preventive Epidemiology, School of Public Health, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Kyoko Kondo
- Osaka City University Hospital, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, Japan
| | - Kazuya Ito
- College of Healthcare Management, 960-4, Takayanagi, Setaka-machi, Miyama-shi, Fukuoka, Japan
| | - Wakaba Fukushima
- Department of Public Health, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan
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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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Negro F. Residual risk of liver disease after hepatitis C virus eradication. J Hepatol 2021; 74:952-963. [PMID: 33276027 DOI: 10.1016/j.jhep.2020.11.040] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 11/20/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022]
Abstract
Treatment of hepatitis C with direct-acting antivirals is safe and highly efficacious, resulting in viral clearance (sustained virological response [SVR]) in the vast majority of patients. Although SVR is mostly permanent and associated with a significant reduction of liver morbidity and mortality, some patients may still suffer from a major risk of progressive liver damage, potentially leading to severe complications - including liver decompensation, hepatocellular carcinoma and death. This concise review discusses some of the most important features of residual liver disease in patients with chronic hepatitis C who have achieved SVR after antiviral therapy.
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Affiliation(s)
- Francesco Negro
- Divisions of Gastroenterology and hepatology, Geneva University Hospitals, Geneva, Switzerland; Divisions of Clinical pathology, Geneva University Hospitals, Geneva, Switzerland.
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Change in γ-glutamyl transpeptidase activity as a useful tool in identifying a group of patients with elevated risk of hepatocellular carcinoma development after DAA treatment of chronic hepatitis C. Clin Exp Hepatol 2021; 7:93-100. [PMID: 34027121 PMCID: PMC8122098 DOI: 10.5114/ceh.2021.104466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 12/16/2020] [Indexed: 12/30/2022] Open
Abstract
Aim of the study Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) incidence will be diminishing due to use of direct acting antiviral agents (DAA), but there is still constant risk for HCC development. Elevated serum g-glutamyl transpeptidase (GGT) activity is associated with increased risk of liver cancer. In our study we tried to determine whether change in GGT activity may be useful in identifying patients with elevated risk of HCC development after DAA treatment. Material and methods The study population consisted of 111 patients with chronic hepatitis C (CHC) treated with DAA. Laboratory tests [alanine aminotransferase (ALT), GGT, a-fetoprotein (AFP)] and liver stiffness measurement (using FibroScan) were performed at the beginning and at the end of therapy. Results Pre-treatment ALT activity, GGT activity and AFP concentration in patients with CHC were directly associated with the stage of liver fibrosis. Elimination of HCV after DAA treatment caused significant reduction in serum GGT activity and was not associated with pre-treatment liver fibrosis. AFP concentration was significantly lower after treatment. It was observed regardless of pre-treatment AFP concentration, but the largest reduction was demonstrated in the group of patients with advanced fibrosis. In multivariate analysis there was no significant difference in GGT activity after treatment only in patients with pre-treatment normal AFP concentration and advanced liver fibrosis. Conclusions Patients who after achieving a sustained virological response (SVR) did not lower both AFP concentration and GGT activity may have higher risk of HCC development. Special monitoring may be required in patients with advanced liver fibrosis and normal AFP concentration before treatment.
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Ochi H, Hiraoka A, Hirooka M, Koizumi Y, Amano M, Azemoto N, Watanabe T, Yoshida O, Tokumoto Y, Mashiba T, Yokota T, Abe M, Michitaka K, Hiasa Y, Joko K. Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria. J Gastroenterol 2021; 56:90-100. [PMID: 33278003 PMCID: PMC7819935 DOI: 10.1007/s00535-020-01747-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/29/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND The effects of direct-acting antivirals (DAAs) on survival and recurrence rates after curative hepatocellular carcinoma (HCC) treatment in patients with hepatitis C virus (HCV) infection remain controversial. METHODS This retrospective, multicenter study involved Child-Pugh class A patients within the Milan criteria who had a first diagnosis of HCC and survived 6 months or longer after undergoing hepatectomy or radiofrequency ablation (RFA). The DAA-treated group (DAA group) included 56 patients, and the DAA-untreated group (untreated group) included 261 patients. The study was conducted using the propensity score-matched (1:2) DAA group and untreated group, 56 and 112 patients, respectively. RESULTS The survival rate at 48 months in the DAA group and the untreated group was 91.0% and 68.7%, respectively, showing significantly better survival in the DAA group (HR: 0.33; 95% CI 0.13-0.84; p = 0.021). The recurrence rate at 48 months was 36.7% and 66.7%, respectively, showing a significantly lower recurrence rate in the DAA group (HR, 0.46; 95% CI 0.27-0.77; p = 0.003). The median albumin-bilirubin (ALBI) score at 3 years post-HCC treatment was - 2.84 in the DAA group and - 2.34 in the untreated group. The ALBI score showed a significant improvement from baseline to 3 years post-HCC treatment (p = 0.001), whereas that in the untreated group showed a significant decline (p = 0.040). CONCLUSIONS DAAs after HCC treatment prevents deterioration of hepatic functional reserve and significantly improves both recurrence and survival rates.
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Affiliation(s)
- Hironori Ochi
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Bunkyo-cho 1, Matsuyama, Ehime Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Kasuga-cho 83, Matsuyama, Ehime Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Michiko Amano
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Bunkyo-cho 1, Matsuyama, Ehime Japan
| | - Nobuaki Azemoto
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Bunkyo-cho 1, Matsuyama, Ehime Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Toshie Mashiba
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Bunkyo-cho 1, Matsuyama, Ehime Japan
| | - Tomoyuki Yokota
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Bunkyo-cho 1, Matsuyama, Ehime Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Kasuga-cho 83, Matsuyama, Ehime Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Bunkyo-cho 1, Matsuyama, Ehime Japan
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Abe K, Wakabayashi H, Nakayama H, Suzuki T, Kuroda M, Yoshida N, Tojo J, Kogure A, Rai T, Saito H, Mukai S, Fujita M, Hayashi M, Takahashi A, Ohira H. Factors associated with hepatocellular carcinoma occurrence after HCV eradication in patients without cirrhosis or with compensated cirrhosis. PLoS One 2020; 15:e0243473. [PMID: 33284844 PMCID: PMC7721183 DOI: 10.1371/journal.pone.0243473] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 11/21/2020] [Indexed: 02/08/2023] Open
Abstract
The present study aimed to investigate the incidence of hepatocellular carcinoma (HCC) and factors related to HCC occurrence after direct-acting antiviral (DAA) treatment in the Fukushima Liver Academic Group (FLAG). We conducted a multicenter retrospective cohort study of 1068 patients without cirrhosis (NC) or with compensated liver cirrhosis (LC) who achieved a sustained virologic response (SVR). First, we compared the cumulative HCC incidence and survival rates in NC (n = 880) and LC (n = 188) patients without a history of HCC treatment. Second, we performed multivariate analysis of factors related to HCC occurrence after DAA treatment. Overall, the average age was 65 years, and the male/female ratio was 511/557. Thirty-nine (4%) patients developed HCC. The cumulative 4-year HCC incidence and survival rates were 3.0% and 99.8% in NC patients and 11.5% and 98.5% in LC patients, respectively. The independent factors affecting HCC occurrence identified by multivariate analysis were the serum albumin (ALB) level before SVR for NC patients and the ALBI score, platelet count, and diabetes before SVR for LC patients. The factors related to HCC occurrence differed between NC and LC patients. Careful surveillance of post-SVR patients with these risk factors is needed.
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Affiliation(s)
- Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
- Department of Internal Medicine, Hanawa Kosei Hospital, Higashishirakawa, Japan
- * E-mail:
| | - Hiroto Wakabayashi
- Department of Gastroenterology, Takeda General Hospital, Aizuwakamatsu, Japan
| | - Haruo Nakayama
- Department of Gastroenterology, Iwaki City Medical Center, Iwaki, Japan
| | - Tomohiro Suzuki
- Department of Gastroenterology, Fukushima Rosai Hospital, Iwaki, Japan
| | - Masahito Kuroda
- Department of Gastroenterology, Fukushima Red Cross Hospital, Fukushima, Japan
| | - Naoe Yoshida
- Department of Internal Medicine, Iwase General Hospital, Sukagawa, Japan
| | | | - Atsuko Kogure
- Department of Gastroenterology, Fujita General Hospital, Date, Japan
| | | | | | - Shinji Mukai
- Department of Gastroenterology, Ohta Nishinouchi Hospital, Koriyama, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Watanabe T, Tokumoto Y, Joko K, Michitaka K, Horiike N, Tanaka Y, Tada F, Kisaka Y, Nakanishi S, Yamauchi K, Yukimoto A, Nakamura Y, Hirooka M, Abe M, Hiasa Y. Sex difference in the development of hepatocellular carcinoma after direct-acting antiviral therapy in patients with HCV infection. J Med Virol 2020; 92:3507-3515. [PMID: 32374470 DOI: 10.1002/jmv.25984] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/02/2020] [Accepted: 04/30/2020] [Indexed: 12/27/2022]
Abstract
Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct-acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log-rank test, P = .007). On multivariate analysis, the fibrosis-4 index (HR = 1.11; 95%CI, 1.042-1.202, P = .002) and posttreatment α-fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046-1.197, P = .001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR = 1.090; 95%CI, 1.024-1.160, P = .007) was an independent factor in male patients. The optimal posttreatment AFP cut-off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut-off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut-off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Kojiro Michitaka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, Matsuyama, Ehime, Japan
| | - Norio Horiike
- Department of Gastroenterology, Saiseikai Imabari Hospital, Imabari, Ehime, Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, Matsuyama, Japan
| | - Fujimasa Tada
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, Matsuyama, Ehime, Japan
| | - Yoshiyasu Kisaka
- Department of Gastroenterology, Uwajima City Hospital, Uwajima, Ehime, Japan
| | - Seiji Nakanishi
- Department of Gastroenterology, Ehime Prefectural Imabari Hospital, Imabari, Ehime, Japan
| | - Kazuhiko Yamauchi
- Department of Gastroenterology, National Hospital Organization Ehime Medical Center, Toon, Ehime, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
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Shiha G. External validation of non-invasive predictors of hepatocellular carcinoma in patients with HCV-related advanced chronic liver disease after oral antivirals. J Hepatol 2020; 73:471-472. [PMID: 32505381 DOI: 10.1016/j.jhep.2020.03.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 03/23/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt; Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Egypt.
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Asahina Y. JSH Guidelines for the Management of Hepatitis C Virus Infection, 2019 Update; Protective Effect of Antiviral Therapy against Hepatocarcinogenesis. Hepatol Res 2020; 50:775-790. [PMID: 32298527 DOI: 10.1111/hepr.13501] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/04/2020] [Accepted: 04/05/2020] [Indexed: 02/08/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology (JSH) drafted the first version of the clinical practice guidelines for the management of hepatitis C virus (HCV) infection in 2012. Since then, we have been publishing updates as new drugs for hepatitis C become available and new indications for existing drugs are added. The new approval of sofosbuvir/velpatasvir prompted us to publish the seventh version of the guidelines in Japanese in March 2019. We also published the first English-language version of the JSH guidelines in 2013 and English versions of updates made to the Japanese-language guidelines in 2014 and 2016. In 2020, the committee has decided to publish a new English version, covering general information about treatment for hepatitis C, drugs used, recommended treatments for chronic hepatitis and cirrhosis, and special populations, such as patients who have renal impairment, are on dialysis, or have developed recurrence of hepatitis C after liver transplantation. Furthermore, the committee has released a separate publication covering the protective effect of antiviral therapy against hepatocarcinogenesis.
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Marasco G, Colecchia A, Silva G, Rossini B, Eusebi LH, Ravaioli F, Dajti E, Alemanni LV, Colecchia L, Renzulli M, Golfieri R, Festi D. Non-invasive tests for the prediction of primary hepatocellular carcinoma. World J Gastroenterol 2020; 26:3326-3343. [PMID: 32655261 PMCID: PMC7327793 DOI: 10.3748/wjg.v26.i24.3326] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/08/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and it is one of the main complications of cirrhosis and portal hypertension. Even in the presence of a well-established follow-up protocol for cirrhotic patients, to date poor data are available on predictive markers for primary HCC occurrence in the setting of compensated advanced chronic liver disease patients (cACLD). The gold standard method to evaluate the prognosis of patients with cACLD, beyond liver fibrosis assessed with histology, is the measurement of the hepatic venous pressure gradient (HVPG). An HVPG ≥10 mmHg has been related to an increased risk of HCC in cACLD patients. However, these methods are burdened by additional costs and risks for patients and are mostly available only in referral centers. In the last decade increasing research has focused on the evaluation of several, simple, non-invasive tests (NITs) as predictors of HCC development. We reviewed the currently available literature on biochemical and ultrasound-based scores developed for the non-invasive evaluation of liver fibrosis and portal hypertension in predicting primary HCC. We found that the most reliable methods to assess HCC risk were the liver stiffness measurement, the aspartate aminotransferase to platelet ratio index score and the fibrosis-4 index. Other promising NITs need further investigations and validation for different liver disease aetiologies.
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Affiliation(s)
- Giovanni Marasco
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Antonio Colecchia
- Unit of Gastroenterology, Borgo Trento University Hospital of Verona, Verona 37126, Italy
| | - Giovanni Silva
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Benedetta Rossini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Leonardo Henry Eusebi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Elton Dajti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Luigina Vanessa Alemanni
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Luigi Colecchia
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Matteo Renzulli
- Radiology Unit, Sant’Orsola Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Rita Golfieri
- Radiology Unit, Sant’Orsola Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Davide Festi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
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Pascut D, Pratama MY, Tiribelli C. HCC occurrence after DAA treatments: molecular tools to assess the post-treatment risk and surveillance. Hepat Oncol 2020; 7:HEP21. [PMID: 32647566 PMCID: PMC7336296 DOI: 10.2217/hep-2020-0010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Devis Pascut
- Fondazione Italiana Fegato - ONLUS, Liver Research Center, AREA Science Park, ss14, Km163.5, Basovizza, 34149 Trieste, Italy
| | - Muhammad Yogi Pratama
- Fondazione Italiana Fegato - ONLUS, Liver Research Center, AREA Science Park, ss14, Km163.5, Basovizza, 34149 Trieste, Italy.,Universitas Hasanuddin, Faculty of Medicine, Makassar, 90245, Indonesia
| | - Claudio Tiribelli
- Fondazione Italiana Fegato - ONLUS, Liver Research Center, AREA Science Park, ss14, Km163.5, Basovizza, 34149 Trieste, Italy
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47
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Huang R, Rao H, Yang M, Gao Y, Wang J, Jin Q, Ma D, Wei L. Noninvasive Measurements Predict Liver Fibrosis Well in Hepatitis C Virus Patients After Direct-Acting Antiviral Therapy. Dig Dis Sci 2020; 65:1491-1500. [PMID: 31654313 DOI: 10.1007/s10620-019-05886-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 10/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Short-time usage of direct-acting antiviral agents (DAA) limited knowledge regarding histological outcomes and predictive values of noninvasive measurements in patients with hepatitis C virus (HCV) after sustained virologic response (SVR) with DAA. AIMS This study aimed to indicate histological changes and assess predictive value of noninvasive measurements for fibrosis in these patients. METHODS HCV patients who achieved SVR by DAA were identified. Pre- and post-SVR clinical and histological data were collected. RESULTS Of patients, 83% (33/40), 38% (15/40) and 83% (33/40) achieved inflammation improvement, fibrosis regression and histological improvement, respectively. Liver stiffness measurements (LSM), APRI, and FIB-4 could predict post-SVR fibrosis well without significant differences. Areas under receiver operating characteristic curves of LSM, APRI, and FIB-4 were 0.78, 0.81, and 0.87 for post-SVR advanced fibrosis (≥ F4) and 0.86, 0.86, and 0.85 for post-SVR cirrhosis (≥ F5), respectively. Pre-SVR LSM, APRI, and FIB-4 values were significantly lower in patients with fibrosis regression (P = 0.003-0.012), while FIB-4 was significantly lower in patients with histological improvement (P = 0.012-0.033). Patients with higher pre-SVR Ishak scores tended to have bigger decline in APRI (P = 0.025) and FIB-4 (P = 0.024) after SVR. CONCLUSIONS DAA could improve liver inflammation and fibrosis of HCV patients in a short time after SVR. LSM, APRI, and FIB-4 predict fibrosis well even after SVR by DAA. Most of the cutoff values for advanced fibrosis (≥ F4) and cirrhosis (≥ F5) of these noninvasive measurements decreased significantly after SVR, maybe because of the inflammation improvement.
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Affiliation(s)
- Rui Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Ming Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China.,Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yinghui Gao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Jian Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Qian Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Danli Ma
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China. .,Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
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48
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Tani J, Morishita A, Sakamoto T, Takuma K, Nakahara M, Fujita K, Oura K, Tadokoro T, Mimura S, Nomura T, Yoneyama H, Kobara H, Himoto T, Tsutsui A, Senoh T, Nagano T, Ogawa C, Moriya A, Deguchi A, Takaguchi K, Masaki T. Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study. Oncol Lett 2020; 19:2205-2212. [PMID: 32194718 PMCID: PMC7038998 DOI: 10.3892/ol.2020.11341] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023] Open
Abstract
Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0-2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa 760-0017, Japan
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kanonji, Kagawa 769-1695, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Marugame, Kagawa 763-8502, Japan
| | - Kouichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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49
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Shigefuku R, Iwasa M, Katayama K, Eguchi A, Kawaguchi T, Shiraishi K, Ito T, Suzuki K, Koreeda C, Ohtake T, Tokumoto Y, Endo R, Kawamura N, Shiraki M, Habu D, Sakai H, Kato A, Nishiguchi S, Moriwaki H, Suzuki K, Takei Y. Hypozincemia is associated with human hepatocarcinogenesis in hepatitis C virus-related liver cirrhosis. Hepatol Res 2019; 49:1127-1135. [PMID: 31240767 DOI: 10.1111/hepr.13388] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/28/2019] [Accepted: 06/05/2019] [Indexed: 02/08/2023]
Abstract
AIM Hypozincemia is associated with the progression of chronic liver diseases, but it is unknown whether hypozincemia promotes human hepatocarcinogenesis. Our aim is to evaluate the serum zinc levels in liver cirrhosis (LC) patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC). METHODS Cirrhotic patients without HCC (n = 299) were enrolled from 14 medical institutes in Japan as a multicenter prospective study (No. 2028). Of the 299 patients, 157 were included in the present study based on reliable and consistent serum zinc levels and no history of oral zinc supplementation. Clinical parameters associated with the development of HCC were determined. Furthermore, the cumulative incidence of HCC was analyzed using Kaplan-Meier methods and was calculated using the log-rank test. A Cox regression analysis was utilized for the multivariate analysis to evaluate the predictors of hepatocarcinogenesis. RESULTS Thirty of 157 patients (19.1%) developed HCC during an observation period of 3 years. Serum zinc levels were significantly decreased in hepatitis C virus-related LC (C-LC) patients with HCC (0.0180). The risk factors for incidence of HCC were hypozincemia (0.0014), high α-fetoprotein (0.0080), low branched chain amino acids-to-tyrosine ratio (0.0128), or female sex (0.0228). Hypozincemia (hazard ratio 1.61, 0.0324) was the only significant predictor of hepatocarcinogenesis by multivariate Cox regression analysis. CONCLUSIONS Hypozincemia is associated with hepatocarcinogenesis in C-LC patients.
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Affiliation(s)
- Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kazuhiro Katayama
- Department of Hepato-Biliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Koichi Shiraishi
- Department of Gastroenterology, Tokai University School of Medicine, Isehara, Japan
| | - Toshifumi Ito
- Department of Gastroenterology, JCHO Osaka Hospital, Osaka, Japan
| | - Kazutomo Suzuki
- Department of Gastroenterology, Shuuwa General Hospital, Kasugabe, Japan
| | - Chizu Koreeda
- Liver Disease Center, Kansai Medical University Medical Center, Moriguchi, Japan
| | - Takaaki Ohtake
- Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Ryujin Endo
- Division of Medical Fundamentals for Nursing, School of Nursing, Iwate Medical University, Morioka, Japan
| | - Naohiro Kawamura
- Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Makoto Shiraki
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Daiki Habu
- Department of Nutritional Medicine, Osaka City University Graduate School of Human Life Science, Osaka, Japan
| | - Hironori Sakai
- Department of Gastroenterology and Hepatology, NHO Beppu Medical Center, Beppu, Japan
| | - Akinobu Kato
- Department of Internal Medicine, Morioka Municipal Hospital, Morioka, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hisataka Moriwaki
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kazuyuki Suzuki
- Department of Nutritional Science, Morioka University, Takizawa, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
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50
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Inoue-Shinomiya E, Murakawa M, Asahina Y, Nakagawa M, Tsuchiya J, Sato A, Tsunoda T, Miyoshi M, Nitta S, Kawai-Kitahata F, Itsui Y, Azuma S, Kakinuma S, Murata K, Mizokami M, Watanabe M. Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. Hepatol Res 2019; 49:500-511. [PMID: 30623518 DOI: 10.1111/hepr.13307] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 12/10/2018] [Accepted: 12/28/2018] [Indexed: 02/08/2023]
Abstract
AIM Although the efficacy of hepatitis C virus (HCV) treatment is improved dramatically by direct-acting antiviral agents (DAAs), the assessment of hepatocellular carcinoma (HCC) remains important. Interferon lambda 3 (IFN-λ3) is associated with liver fibrosis and inflammation in chronic hepatitis C (CHC) patients, but its impact on carcinogenesis remains controversial and little is known about its effects after viral clearance. To determine the contribution of IFN-λ3 to hepatocarcinogenesis after HCV clearance, we analyzed IFNL3 genotypes and serial serum IFN-λ3 levels in CHC patients who achieved sustained virologic responses (SVR). METHODS This study comprised 201 CHC patients treated with DAAs. Serum samples were collected sequentially and IFN-λ3 levels were quantified by chemiluminescence enzyme immunoassay. The IFNL3 polymorphism (rs8099917) was genotyped in 195 patients. RESULTS One hundred and twenty-five patients were rs8099917 T/T and 70 were non-T/T. Serum IFN-λ3 levels did not differ significantly with IFNL3 genotype, dropped markedly by 1 week and remained low up to 24 weeks after the end of treatment. Interferon-λ3 levels were significantly higher after viral clearance in patients who developed HCC and were associated with a higher potential for hepatocarcinogenesis, such as a higher frequency of non-hypervascular hypointensive nodules (P = 0.046), higher stages of liver fibrosis (P < 0.001), and higher post-treatment levels of Wisteria floribunda agglutinin positive Mac-2 binding protein (P < 0.001) and alanine aminotransferase (P < 0.001). CONCLUSIONS Serum IFN-λ3 levels after HCV clearance are associated with the potential for HCC development. Interferon-λ3 could be helpful for elucidating the relationships among immunologic status, liver fibrosis, liver inflammation, and hepatocarcinogenesis, after achieving SVR.
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Affiliation(s)
- Emi Inoue-Shinomiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Clinical Laboratory, Medical Hospital of Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomoyuki Tsunoda
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Itsui
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazumoto Murata
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan.,Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Nasushiobara, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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