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Wang HW, Zeng YS, Huang CF, Chen CY, Kuo HT, Tseng KC, Mo LR, Cheng PN, Tai CM, Hung CH, Lo CC, Chen CH, Lee PL, Yang CC, Chen CT, Lin CY, Hsieh TY, Chong LW, Lin CL, Hu JT, Yang SS, Kao JH, Liu CJ, Chuang WL, Huang JF, Yeh ML, Dai CY, Huang YH, Lin HC, Bair MJ, Wang SJ, Huang CW, Tsai MC, Wang CC, Su WW, Lin CW, Lin CL, Chu CH, Yu ML, Peng CY. Posttreatment FIB-4 score change predicts hepatocellular carcinoma in chronic hepatitis C patients: Findings from the Taiwan hepatitis C registry program. J Formos Med Assoc 2025:S0929-6646(25)00056-7. [PMID: 40023754 DOI: 10.1016/j.jfma.2025.02.014] [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: 11/11/2024] [Revised: 01/27/2025] [Accepted: 02/07/2025] [Indexed: 03/04/2025] Open
Abstract
PURPOSE This study investigated whether Fibrosis-4 (FIB-4) score and its change can serve as predictors of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C (CHC) infection receiving direct-acting antivirals (DAAs). METHODS This study identified 9679 patients who completed DAA treatment and achieved sustained virologic response (SVR) from the Taiwan Nationwide Real-World HCV Registry Program, and their risk of HCC was analyzed. RESULTS Multivariable Cox regression analyses identified diabetes mellitus (DM), alpha-fetoprotein (AFP) level, and FIB-4 score as independent predictors of HCC in both Model 1 (baseline) and Model 2 (SVR). Change in FIB-4 score (△FIB-4) of < -0.9086 from baseline to SVR achievement was a significant predictor of HCC only in Model 2 (SVR). In Model 2 (SVR), DM (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 1.04-2.26, p = 0.033), FIB-4 score (≥3.25 vs. <3.25; HR: 2.40, 95% CI: 1.63-3.53, p < 0.001), △FIB-4 (greater reduction: <-0.9086 vs. smaller reduction: ≥-0.9086; HR: 1.85, 95% CI: 1.25-2.74, p = 0.002), and AFP level (≥20 vs. <20 ng/mL; HR: 16.40, 95% CI: 9.16-29.36, p < 0.001) were significant predictors of HCC. At 3 years, the cumulative HCC incidence was 10.67% in patients with an FIB-4 score of ≥3.25 upon achieving SVR and △FIB-4 of < -0.9086 and 1.72% in those with an FIB-4 score of <3.25 upon achieving SVR and △FIB-4 of ≥ -0.9086. CONCLUSIONS Posttreatment FIB-4 score and its change from baseline can be used to stratify HCC risk in patients with CHC receiving DAAs.
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Affiliation(s)
- Hung-Wei Wang
- School of Medicine, China Medical University, Taichung, Taiwan; Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Syuan Zeng
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chi-Yi Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Taiwan
| | - Hsing-Tao Kuo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Kuo-Chih Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Chiayi, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
| | | | - Pin-Nan Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Ming Tai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chia-Yi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ching-Chu Lo
- Division of Gastroenterology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taiwan
| | - Pei-Lun Lee
- Liouying Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Chi-Chieh Yang
- Department of Gastroenterology, Division of Internal Medicine, Show Chwan Memorial Hospital, Taiwan
| | - Chun-Ting Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital Penghu Branch, National Defense Medical Center, Taipei, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Lee-Won Chong
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Chih-Lang Lin
- Liver Research Unit, Department of Hepato-Gastroenterology and Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Chang Gung University, College of Medicine, Keelung, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jia-Horng Kao
- Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hsiang Huang
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Han-Chieh Lin
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Szu-Jen Wang
- Division of Gastroenterology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung, Taiwan
| | - Chien-Wei Huang
- Division of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan
| | - Ming-Chang Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Chi Wang
- Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Taiwan
| | - Wei-Wen Su
- Department of Gastroenterology and Hepatology, Changhua Christian Hospital, Taiwan
| | - Chih-Wen Lin
- Division of Gastroenterology and Hepatology, E-Da Dachang Hospital, and School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Renai Branch, Taipei City Hospital, Taipei, Taiwan
| | | | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan; Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
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Smirne C, Crobu MG, Landi I, Vercellino N, Apostolo D, Pinato DJ, Vincenzi F, Minisini R, Tonello S, D’Onghia D, Ottobrelli A, Martini S, Bracco C, Fenoglio LM, Campanini M, Berton AM, Ciancio A, Pirisi M. Chronic Hepatitis C Infection Treated with Direct-Acting Antiviral Agents and Occurrence/Recurrence of Hepatocellular Carcinoma: Does It Still Matter? Viruses 2024; 16:1899. [PMID: 39772206 PMCID: PMC11680226 DOI: 10.3390/v16121899] [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: 10/09/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Maria Grazia Crobu
- Laboratory of Molecular Virology, Maggiore della Carità Hospital, 28100 Novara, Italy;
- Clinical Biochemistry Laboratory, City of Health and Science University Hospital, 10126 Turin, Italy
| | - Irene Landi
- Emergency Medicine Department, Michele e Pietro Ferrero Hospital, 12060 Verduno, Italy;
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Daria Apostolo
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - David James Pinato
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London SW7 2AZ, UK
| | - Federica Vincenzi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Stelvio Tonello
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Davide D’Onghia
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
| | - Antonio Ottobrelli
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
| | - Silvia Martini
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
| | - Christian Bracco
- Department of Internal Medicine, Santa Croce e Carle Hospital, 12100 Cuneo, Italy; (C.B.); (L.M.F.)
| | - Luigi Maria Fenoglio
- Department of Internal Medicine, Santa Croce e Carle Hospital, 12100 Cuneo, Italy; (C.B.); (L.M.F.)
| | - Mauro Campanini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Alessandro Maria Berton
- Division of Endocrinology, Diabetes and Metabolism, City of Health and Science University Hospital, 10126 Turin, Italy;
| | - Alessia Ciancio
- Gastroenterology Unit, City of Health and Science University Hospital, 10126 Turin, Italy; (A.O.); (S.M.); (A.C.)
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (N.V.); (D.A.); (D.J.P.); (F.V.); (R.M.); (S.T.); (D.D.); (M.C.); (M.P.)
- Internal Medicine Unit, Maggiore della Carità Hospital, 28100 Novara, Italy
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Vilar FC, Donadi E, da Fonseca BAL, Freitas JCDOC, Borducchi ALGZ, Santana RDC. HLA-G liver expression in chronically HIV/hepatitis C-coinfected individuals. Ann Hepatol 2024; 30:101755. [PMID: 39631457 DOI: 10.1016/j.aohep.2024.101755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 09/04/2024] [Accepted: 10/23/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION AND OBJECTIVES Hepatitis C-induced liver disease represents a significant threat to the survival of people living with HIV. HIV/HCV-coinfected individuals have a more rapid progression to cirrhosis and its complications than HCV monoinfected patients. Although the underlying mechanisms remain unclear, HLA-G, a non-classical class I HLA molecule, has a well-recognized property to down-regulate the immune response against viruses and may favor the progression of chronic hepatitis C. MATERIALS AND METHODS We analyzed HLA-G expression in 59 liver specimens of patients harboring chronic HCV and HIV coinfection and stratified the findings according to clinical and histopathological features. RESULTS Genotype 1 was the most prevalent (88%); the HLA-G expression was observed in 38 (64%) liver specimens, and it was more frequent in more severe stages than in milder stages of chronic hepatitis (94,1% x 55%; p<0.01). HLA-G expression in the liver was not correlated to antiviral response to hepatitis C therapy with pegylated-IFN-α plus ribavirin. CONCLUSIONS HLA-G expression in the context of HCV/HIV coinfection is a complex process modulated by many factors. HLA-G expression may play a role in the mechanisms that facilitate disease progression and may contribute to the deterioration of the immune response against HCV in individuals living with HIV.
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Affiliation(s)
- Fernando Crivelenti Vilar
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Eduardo Donadi
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | | | | | | | - Rodrigo de Carvalho Santana
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
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Hassan AM, Orabi HH, Abdel-Gawad M, Mohamed O, Sawy SS, Abdelmeguid MM, Bashir MA, Abdelrazzak E, Ead K, Haridy MA. Changes in Vascular Endothelial Growth Factor and Development of Hepatocellular Carcinoma in Direct-Acting Antiviral Drugs (DAAs)-Treated Hepatitis C Virus (HCV) Patients. Cureus 2024; 16:e75982. [PMID: 39830567 PMCID: PMC11742266 DOI: 10.7759/cureus.75982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/22/2025] Open
Abstract
Background There is ongoing debate regarding the impact of direct-acting antiviral drugs (DAAs) on the occurrence of de novo hepatocellular carcinoma (HCC). Vascular endothelial growth factor (VEGF) plays a crucial role in the development and angiogenesis of HCC. Aim This study aims to evaluate dynamic changes in vascular endothelial growth factor (VEGF) levels at different point times during and after treatment of HCV to evaluate the risk of de novo HCC in DAAs-treated HCV patients. Methods This prospective cohort study was conducted on 60 HCV-infected patients; 30 patients had early fibrosis (F1-F2) and 30 patients had advanced fibrosis (F3-F4). HCV-RNA, aspartate aminotransferase (AST) to platelet ratio index (APRI), and fibrosis-4 index scores, liver function tests, serum VEGF, alpha-fetoprotein (AFP), and abdominal ultrasound were done at baseline, 4 weeks after starting treatment, at the end of treatment, and 12 weeks after treatment. Results VEGF was significantly decreased after completion of treatment (78.94± 10.03) compared to its baseline level (103.17 ± 33.89 pg/ml). Conclusion No de-novo hepatic focal lesion was detected during and up to 12 weeks after completion of treatment. The treatment of HCV by DAAs was associated with a significant decrease in VEGF and AFP levels and an improvement in liver enzymes and fibrosis scores.
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Affiliation(s)
- Amro M Hassan
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | - Heba H Orabi
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | - Muhammad Abdel-Gawad
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | - Omran Mohamed
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | - Safwat S Sawy
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | | | - Mohamed A Bashir
- Department of Clinical Pathology, Al-Azhar University, Assiut, EGY
| | - Emad Abdelrazzak
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | - Khalid Ead
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
| | - Mustafa A Haridy
- Department of Hepatology, Gastroenterology, and Infectious Diseases, Al-Azhar University, Assiut, EGY
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Brzdęk M, Zarębska-Michaluk D, Kukla M, Janocha-Litwin J, Dybowska D, Janczewska E, Lorenc B, Berak H, Mazur W, Tudrujek-Zdunek M, Klapaczyński J, Piekarska A, Sitko M, Laurans Ł, Parfieniuk-Kowerda A, Flisiak R. Real-world experience with direct-acting antiviral therapy in HCV-infected patients with cirrhosis and esophageal varices. Pharmacol Rep 2024; 76:1114-1129. [PMID: 39162985 PMCID: PMC11387439 DOI: 10.1007/s43440-024-00639-9] [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: 05/03/2024] [Revised: 08/11/2024] [Accepted: 08/12/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection affects 50 million people worldwide with around 242,000 deaths annually, mainly due to complications such as cirrhosis and hepatocellular carcinoma (HCC). Portal hypertension (PH) caused by cirrhosis leads to severe consequences, including esophageal varices (EV). This study aimed to evaluate the effectiveness and safety of direct-acting antiviral (DAA) treatment in patients with and without EV. METHODS This retrospective analysis involved consecutive HCV-infected adults undergoing DAA therapy at 22 Polish hepatology centers from July 1, 2015, to December 31, 2022. Patients with cirrhosis were categorized based on the presence of EV diagnosed by gastroscopy. Treatment effectiveness was measured by sustained virologic response (SVR), with safety outcomes monitored for 12 weeks post-treatment. RESULTS A population of 3393 HCV-infected patients with cirrhosis was divided into groups with (A, n = 976) and without (B, n = 2417) EV. Group A showed a significantly higher prevalence of comorbidities and concomitant medications. Genotype (GT)1b infections predominated in both groups, and GT3 infections were more common in the EV group. Group A exhibited more severe liver disease, and higher rates of decompensation, HCC, and HBV co-infection. SVR was significantly higher in group B (91.5% vs. 96.3%, p < 0.0001). Male gender, GT3, EV presence, and Child-Pugh grade B were identified as independent negative SVR predictors. Group A had a worse safety profile, with notably higher adverse event incidence and mortality. CONCLUSIONS DAA therapies are highly effective and well tolerated in patients with cirrhosis, but EV presence predicts poorer virologic responses.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, aleja IX Wieków Kielc 19A, Kielce, 25-317, Poland.
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases and Allergology, Jan Kochanowski University, Kielce, 25- 317, Poland
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagiellonian University Medical College, Kraków, 31-688, Poland
- Department of Endoscopy, University Hospital, Kraków, 30-688, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, 50- 367, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, 87-100, Poland
- Voivodeship Infectious Observation Hospital in Bydgoszcz, Bydgoszcz, 85-030, Poland
| | - Ewa Janczewska
- Department of Basic Medical Sciences, School of Public Health in Bytom, Medical University of Silesia, Katowice, 40-055, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University, Gdańsk, 80-214, Poland
| | - Hanna Berak
- Outpatient Clinic, Hospital for Infectious Diseases in Warsaw, Warsaw, 01-201, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases in Chorzów, Medical University of Silesia, Katowice, 40-055, Poland
| | | | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, The National Institute of Medicine of the Ministry of Interior and Administration, Warszawa, 02-507, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź, 90- 419, Poland
| | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków, 31- 088, Poland
| | - Łukasz Laurans
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, 70-204, Poland
- Multidisciplinary Regional Hospital in Gorzów Wielkopolski, Gorzów Wielkopolski, 66-400, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, 15-089, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, 15-089, Poland
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Piñero F, Mauro E, Casciato P, Forner A. From evidence to clinical practice: Bridging the gap of new liver cancer therapies in Latin America. Ann Hepatol 2024; 29:101185. [PMID: 38042481 DOI: 10.1016/j.aohep.2023.101185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 10/26/2023] [Indexed: 12/04/2023]
Abstract
The most common primary liver tumors are hepatocellular carcinoma and cholangiocarcinoma. They constitute the sixth most common neoplasia and the third cause of cancer-related deaths worldwide. Although both tumors may share etiologic factors, diagnosis, prognostic factors, and treatments, they differ substantially in determining distinctive clinical management. In recent years, significant advances have been made in the management of these neoplasms, particularly in advanced stages. In this review, we focus on the most relevant diagnostic, prognostic, and treatment aspects of both, hepatocellular carcinoma and cholangiocarcinoma, underlying their applicability in Latin America.
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Affiliation(s)
- Federico Piñero
- Hospital Universitario Austral, Austral University, School of Medicine, Buenos Aires, Argentina.
| | - Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | | | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain; University of Barcelona, Barcelona, Spain.
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Farouk F, Ibrahim IM, Sherif S, Abdelhamed HG, Sharaky M, Al-Karmalawy AA. Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC-MS/MS cancer cell entrapment assays. Chem Biol Drug Des 2024; 103:e14500. [PMID: 38467555 DOI: 10.1111/cbdd.14500] [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: 10/07/2023] [Revised: 02/04/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024]
Abstract
Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.
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Affiliation(s)
- Faten Farouk
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Ibrahim M Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Salma Sherif
- Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, Egypt
| | | | - Marwa Sharaky
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Ahmed A Al-Karmalawy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt
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8
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Nakagawa C, Oikawa T, Yamada K, Tsubota A, Saeki C, Katagiri K, Tago N, Kamioka H, Ueda K, Haruki K, Furukawa K, Nakano M, Torisu Y, Ikegami T, Yoshida K, Saruta M. Protein kinase C delta enhances the diagnostic performance of hepatocellular carcinoma. Biomarkers 2024; 29:55-67. [PMID: 38361436 DOI: 10.1080/1354750x.2024.2312990] [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: 10/23/2023] [Accepted: 01/27/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND The conventional markers for hepatocellular carcinoma (HCC), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), have several limitations; both have low sensitivity in patients with early-stage HCC; low sensitivity for AFP with HCC after eliminating hepatitis C virus (HCV); low specificity for DCP in patients with non-viral HCC, which is increasing worldwide; low specificity for AFP in patients with liver injury; and low specificity for DCP in patients treated with warfarin. To overcome these issues, the identification of novel biomarkers is an unmet need. OBJECTIVE This study aimed to assess the usefulness of serum protein kinase C delta (PKCδ) for detecting these HCCs. METHODS PKCδ levels were measured using a sandwich enzyme-linked immunosorbent assay in 363 chronic liver disease (CLD) patients with and without HCC. RESULTS In both viral and non-viral CLD, PKCδ can detect HCCs with high sensitivity and specificity, particularly in the very early stages. Notably, the value and sensitivity of PKCδ were not modified by HCV elimination status. Liver injury and warfarin administration, which are known to cause false-positive results for conventional markers, did not modify PKCδ levels. CONCLUSIONS PKCδ is an enhanced biomarker for the diagnosis of HCC that compensates for the drawbacks of conventional markers.
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Affiliation(s)
- Chika Nakagawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kohji Yamada
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Akihito Tsubota
- Project Research Units, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kuniko Katagiri
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoko Tago
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Kamioka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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9
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Shree Harini K, Ezhilarasan D. Flavonoids-based nanomedicines for the treatment of liver fibrosis: A recent progress. J Drug Deliv Sci Technol 2024; 93:105467. [DOI: 10.1016/j.jddst.2024.105467] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Ichikawa S, Motosugi U, Sawai Y, Ishida H, Imai Y, Kozaka K, Tsurusaki M, Sofue K, Murakami T, Kawai N, Matsuo M, Fukukura Y, Mawatari S, Shimizu T, Morisaka H, Inoue T, Goshima S. Magnetic resonance imaging-based risk factors of hepatocellular carcinoma after direct-acting antiviral therapy: A multicenter observational study. Hepatol Res 2024; 54:43-53. [PMID: 37676063 DOI: 10.1111/hepr.13964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023]
Abstract
AIM To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct-acting antiviral (DAA) therapy. METHODS We enrolled patients with chronic hepatitis C who underwent direct-acting antiviral therapy and achieved sustained virologic response at 12 weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni- and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid-enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. RESULTS The final study cohort comprised 482 patients (median age 70.5 years; 242 men). The median follow-up period was 36.8 months. Among 482 patients, 96 developed HCC (19.9%). The 1-, 3-, and 5-year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p < 0.001-0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1- and 3-year cumulative HCC development rates were 14.2% and 62.2%, respectively). CONCLUSION History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct-acting antiviral therapy.
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Affiliation(s)
- Shintaro Ichikawa
- Department of Radiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Department of Radiology, University of Yamanashi, Chuo, Japan
| | - Utaroh Motosugi
- Department of Radiology, University of Yamanashi, Chuo, Japan
- Department of Diagnostic Radiology, Kofu Kyoritsu Hospital, Kofu, Japan
| | - Yoshiyuki Sawai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan
| | - Hisashi Ishida
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan
| | - Kazuto Kozaka
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Masakatsu Tsurusaki
- Department of Radiology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Keitaro Sofue
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takamichi Murakami
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | | | | | - Yoshihiko Fukukura
- Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Seiichi Mawatari
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Tatsuya Shimizu
- Department of Radiology, University of Yamanashi, Chuo, Japan
| | | | - Taisuke Inoue
- First Department of Internal Medicine, University of Yamanashi, Chuo, Japan
| | - Satoshi Goshima
- Department of Radiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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11
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Alghamdi AS, Alghamdi H, Alserehi HA, Babatin MA, Alswat KA, Alghamdi M, AlQutub A, Abaalkhail F, Altraif I, Alfaleh FZ, Sanai FM. SASLT guidelines: Update in treatment of hepatitis C virus infection, 2024. Saudi J Gastroenterol 2024; 30:S1-S42. [PMID: 38167232 PMCID: PMC10856511 DOI: 10.4103/sjg.sjg_333_23] [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: 09/20/2023] [Revised: 11/27/2023] [Accepted: 12/03/2023] [Indexed: 01/05/2024] Open
Abstract
ABSTRACT Hepatitis C virus (HCV) infection has been a major global health concern, with a significant impact on public health. In recent years, there have been remarkable advancements in our understanding of HCV and the development of novel therapeutic agents. The Saudi Society for the Study of Liver Disease and Transplantation formed a working group to develop HCV practice guidelines in Saudi Arabia. The methodology used to create these guidelines involved a comprehensive review of available evidence, local data, and major international practice guidelines regarding HCV management. This updated guideline encompasses critical aspects of HCV care, including screening and diagnosis, assessing the severity of liver disease, and treatment strategies. The aim of this updated guideline is to assist healthcare providers in the management of HCV in Saudi Arabia. It summarizes the latest local studies on HCV epidemiology, significant changes in virus prevalence, and the importance of universal screening, particularly among high-risk populations. Moreover, it discusses the promising potential for HCV elimination as a public health threat by 2030, driven by effective treatment and comprehensive prevention strategies. This guideline also highlights evolving recommendations for advancing disease management, including the treatment of HCV patients with decompensated cirrhosis, treatment of those who have previously failed treatment with the newer medications, management in the context of liver transplantation and hepatocellular carcinoma, and treatment for special populations.
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Affiliation(s)
- Abdullah S. Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahad Hospital, Jeddah, Saudi Arabia
| | - Hamdan Alghamdi
- Hepatology Section, Hepatobiliary Sciences and Organs Transplant Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Haleema A. Alserehi
- General Directorate of Communicable Diseases, Ministry of Health, Riyadh, Saudi Arabia
| | - Mohammed A. Babatin
- Department of Medicine, Gastroenterology Unit, King Fahad Hospital, Jeddah, Saudi Arabia
| | - Khalid A. Alswat
- Liver Disease Research Center, and Riyadh, Saudi Arabia
- College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Alghamdi
- Department of Medicine, Division of Gastroenterology, King Fahd Military Complex, Dhahran, Saudi Arabia
| | - Adel AlQutub
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Faisal Abaalkhail
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, Al Faisal University, Riyadh, Saudi Arabia
| | - Ibrahim Altraif
- Hepatology Section, Hepatobiliary Sciences and Organs Transplant Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | | | - Faisal M. Sanai
- Liver Disease Research Center, and Riyadh, Saudi Arabia
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
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12
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Flamm S, Lawitz E, Borg B, Charlton M, Landis C, Reddy KR, Shiffman M, Alsina A, Chang C, Ravendhran N, Hernandez C, Hézode C, Scherbakovsky S, Mercier RC, Samuel D. Efficacy and Safety of Sofosbuvir/Velpatasvir Plus Ribavirin in Patients with Hepatitis C Virus-Related Decompensated Cirrhosis. Viruses 2023; 15:2026. [PMID: 37896803 PMCID: PMC10611233 DOI: 10.3390/v15102026] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 10/29/2023] Open
Abstract
A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child-Turcotte-Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3-4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.
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Affiliation(s)
- Steven Flamm
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL 60612, USA
| | - Eric Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX 78215, USA
| | - Brian Borg
- Southern Therapy and Advanced Research LLC, Jackson, MS 39216, USA
| | | | - Charles Landis
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, WA 98101, USA
| | - K. Rajender Reddy
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mitchell Shiffman
- Bon Secours Mercy Health, Liver Institute of Virginia, Richmond, VA 23226, USA
| | - Angel Alsina
- Tampa General Medical Group, Tampa, FL 33609, USA
| | - Charissa Chang
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | | | | | | | | | - Didier Samuel
- Centre Hépatobiliaire, Hôpital Paul-Brousse, Inserm Research Unit 1193, Université Paris-Saclay, 94800 Villejuif, France
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13
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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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14
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Kim NJ, Vutien P, Cleveland E, Cravero A, Ioannou GN. Fibrosis Stage-specific Incidence of Hepatocellular Cancer After Hepatitis C Cure With Direct-acting Antivirals: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2023; 21:1723-1738.e5. [PMID: 35525392 PMCID: PMC9636072 DOI: 10.1016/j.cgh.2022.04.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) eradication with direct-acting antivirals reduces hepatocellular carcinoma (HCC) risk. Pooled HCC incidence rates by cirrhosis status and fibrosis stage have not been estimated using meta-analysis. METHODS We searched PubMed, Web of Science, Embase, and Cochrane Library from January 1, 2014 to December 31, 2020 to identify studies assessing HCC incidence or outcomes by cirrhosis status, in adults with HCV who achieved sustained virologic response (SVR) after direct-acting antivirals. Pooled estimates were obtained using random-effects modeling. Subgroup, sensitivity, and meta-regression analyses were performed to evaluate heterogeneity. RESULTS We included 31 studies involving 27,711 patients with cirrhosis (mean follow-up, 2.1 years) and 11 studies involving 32,123 patients without cirrhosis (mean follow-up, 2.6 years). HCC incidence was 2.99/100 person-years (95% confidence interval [CI], 2.52-3.54; I2 = 75%) in patients with cirrhosis, 0.47/100 person-years (95% CI, 0.32-0.70, I2 = 71%) in patients without cirrhosis, and 0.63/100 person-years (95% CI: 0.34-1.20, I2 = 0%) in stage 3 (F3) fibrosis. Among patients with cirrhosis, HCC incidence was highest in studies with <1 year of follow-up (6.17/100 person-years [95% CI, 3.73-10.19]) and progressively lower in studies with longer follow-up (1-2 years: 2.75/100 person-years [95% CI, 2.48-3.06]; 2-3 years: 2.90/100 person-years [95% CI, 1.90-4.44]; ≥3 years: 1.83/100 person-years [95% CI, 0.88-3.80]). CONCLUSION Pooled HCC incidence after SVR in patients with cirrhosis was very high (2.99/100 person-years) but may be declining as longer time accrues after SVR. In patients without cirrhosis, including F3 fibrosis, HCC incidence was lower than thresholds associated with cost-effective HCC screening. In patients with F3 fibrosis, the lack of between-study heterogeneity provides strong evidence that HCC screening may not be warranted.
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Affiliation(s)
- Nicole J Kim
- Division of Gastroenterology, University of Washington, Seattle, Washington.
| | - Philip Vutien
- Division of Gastroenterology, University of Washington, Seattle, Washington
| | - Erin Cleveland
- Division of Gastroenterology, University of Washington, Seattle, Washington
| | - Anne Cravero
- Department of Medicine, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, University of Washington, Seattle, Washington; Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
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15
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Marie MS, Shousha HI, Abdelrazek W, Hassany M, Dabees H, Abdelghafour R, Aboganob WM, Said M. Prediction of hepatic decompensation and hepatocellular carcinoma after direct-acting antiviral therapy in patients with hepatitis C-related liver cirrhosis: a cohort study. EGYPTIAN LIVER JOURNAL 2023; 13:12. [DOI: 10.1186/s43066-023-00247-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 02/19/2023] [Indexed: 03/05/2023] Open
Abstract
AbstractAimThis study aimed to evaluate the rate of hepatic decompensation and de novo HCC and identify their independent factors in HCV genotype 4-infected patients with compensated liver cirrhosis following successful direct-acting antiviral (DAA) therapy.MethodsThis prospective cohort study included 1789 patients with HCV genotype 4-related compensated liver cirrhosis who achieved viral eradication after DAAs. Baseline and follow-up clinical, laboratory, albumin-bilirubin score (ALBI), and abdominal ultrasound were recorded to detect hepatic decompensation and de novo HCC. Logistic regression was performed to evaluate the variables associated with decompensation and HCC.ResultsDuring the 24-month period of follow-up, 184 (10.28%) patients developed hepatic decompensation. Ascites was the commonest presentation. Baseline serum albumin, bilirubin, and platelet count were the independent factors associated with hepatic decompensation (P-values 0.022, 0.03, and < 0.001, respectively). A formula was developed for the prediction of decompensation using these 3 factors (AUC: 0.641 at cutoff 0.1098969 with a sensitivity of 59.9% and specificity of 61.7%). Pre-treatment ALBI score could predict decompensation at cutoff value − 2.5184, AUC 0.609, sensitivity 58.3%, and specificity 59.7%. Post-treatment ALBI score could predict hepatic decompensation after DAA therapy at cutoff value − 2.9521, AUC 0.597, sensitivity 48.1%, and specificity 75.5%. Sixteen (0.9%) patients developed de novo HCC. Age (odds ratio: 1.061, 95%, confidence interval: 1–1.126) and male gender (OR 3.450, 95% CI 1.105–10.769) were the independent factors associated with the development of de novo HCC but not the ALBI score.ConclusionBaseline demographic and laboratory data could predict hepatic decompensation and HCC in patients with compensated liver cirrhosis after successful DAA therapy
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16
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Abdelhamed W, El-Kassas M. Hepatocellular carcinoma and hepatitis C virus treatments: The bold and the beautiful. J Viral Hepat 2023; 30:148-159. [PMID: 36461645 DOI: 10.1111/jvh.13778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/07/2022] [Accepted: 11/26/2022] [Indexed: 12/04/2022]
Abstract
The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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17
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Dong MP, Thuy LTT, Hoang DV, Hai H, Hoang TH, Sato-Matsubara M, Hieu VN, Daikoku A, Hanh NV, Urushima H, Dat NQ, Uchida-Kobayashi S, Enomoto M, Ohtani N, Tamori A, Kawada N. Soluble Immune Checkpoint Protein CD27 Is a Novel Prognostic Biomarker of Hepatocellular Carcinoma Development in Hepatitis C Virus-Sustained Virological Response Patients. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:1379-1396. [PMID: 35963463 DOI: 10.1016/j.ajpath.2022.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 06/08/2022] [Accepted: 07/07/2022] [Indexed: 06/15/2023]
Abstract
Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.
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Affiliation(s)
- Minh Phuong Dong
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Dinh Viet Hoang
- Department of Anesthesiology, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Hoang Hai
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Truong Huu Hoang
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan; Department of Pain Medicine and Palliative Care, Cancer Institute, 108 Military Central Hospital, Hanoi, Vietnam
| | - Misako Sato-Matsubara
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Vu Ngoc Hieu
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsuko Daikoku
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ngo Vinh Hanh
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ninh Quoc Dat
- Department of Pediatrics, Hanoi Medical University, Hanoi, Vietnam
| | - Sawako Uchida-Kobayashi
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Naoko Ohtani
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Akihiro Tamori
- 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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18
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Olveira Martín A, García Montes ML, Sanchez-Azofra M. Risk of hepatocellular carcinoma in patients with chronic hepatitis c infection and stage 3 fibrosis after sustained virological response. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:309-311. [PMID: 35510319 DOI: 10.17235/reed.2022.8840/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Evidence on the risk of hepatocellular carcinoma (HCC) in patients with stage 3 liver fibrosis (F3) and SVR is scarce and continues to generate uncertainty. Furthermore, the distinction between F3 and F4 disease is complex. Consequently, the latest international guidelines recommend using the same screening protocol for HCC after SVR in both F3 and F4 patients. However, the risk of HCC in these groups is possibly different and maintaining screening for HCC in this population indefinitely generates an excessive burden for the health system. This editorial aims to review the available evidence on this topic.
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19
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Fujii H, Kimura H, Hasebe C, Akahane T, Satou T, Kusakabe A, Kojima Y, Kondo M, Marusawa H, Kobashi H, Tsuji K, Ogawa C, Uchida Y, Joko K, Mitsuda A, Kurosaki M, Izumi N. Real‐world long‐term analysis of daclatasvir plus asunaprevir in patients with hepatitis C virus infection. JGH Open 2022; 6:344-352. [PMID: 35601120 PMCID: PMC9120887 DOI: 10.1002/jgh3.12749] [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: 01/17/2022] [Revised: 03/30/2022] [Accepted: 04/23/2022] [Indexed: 11/10/2022]
Abstract
Background and Aim Methods Results Conclusions
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Kyoto Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Kyoto Japan
| | - Chitomi Hasebe
- Department of Gastroenterology Asahikawa Red Cross Hospital Asahikawa Japan
| | - Takehiro Akahane
- Department of Gastroenterology Japanese Red Cross Ishinomaki Hospital Ishinomaki Japan
| | - Takashi Satou
- Department of Gastroenterology Nasu Red Cross Hospital Otawara Japan
| | - Atsunori Kusakabe
- Department of Gastroenterology Nagoya Daini Red Cross Hospital Nagoya Japan
| | - Yuji Kojima
- Department of Gastroenterology and Hepatology Ise Red Cross Hospital Ise Japan
| | - Masahiko Kondo
- Department of Gastroenterology Otsu Red Cross Hospital Siga Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology Osaka Red Cross Hospital Osaka Japan
| | - Haruhiko Kobashi
- Department of Hepatology Japanese Red Cross Okayama Hospital Okayama Japan
| | - Keiji Tsuji
- Department of Gastroenterology Hiroshima Red Cross Hospital and Atomic‐Bomb Survivors Hospital Hiroshima Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology Takamatsu Red Cross Hospital Takamatsu Japan
| | - Yasushi Uchida
- Department of Gastroenterology Matsue Red Cross Hospital Matsue Japan
| | - Kouji Joko
- Center for Liver and Biliary Diseases Matsuyama Red Cross Hospital Ehime Japan
| | - Akeri Mitsuda
- Department of Gastroenterology Japanese Red Cross Tottori Hospital Tottori Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Musashino Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology Musashino Red Cross Hospital Musashino Japan
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20
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Cisneros-Garza L, González-Huezo M, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño G, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez M, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva J, Gabutti-Thomas J, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández P, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz M, Ruíz-García E, Sánchez-Ávila J, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:216-234. [DOI: 10.1016/j.rgmxen.2021.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
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21
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Cisneros-Garza LE, González-Huezo MS, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño GA, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez MA, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva JA, Gabutti-Thomas JA, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández PA, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz MA, Ruíz-García E, Sánchez-Ávila JF, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:216-234. [PMID: 35431142 DOI: 10.1016/j.rgmx.2021.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.
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Affiliation(s)
- L E Cisneros-Garza
- Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico
| | | | - C Moctezuma-Velázquez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - M Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - G A Álvarez-Treviño
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | | | - L Bornstein-Quevedo
- InmunoQ, Laboratorio de Patología, Inmunohistoquímica y Biología Molecular, Mexico City, Mexico
| | | | | | | | | | | | - J A Gabutti-Thomas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - D Huitzil-Meléndez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - P A López-Hernández
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, Mexico
| | | | - M A Morales-Ruiz
- Centro Oncológico Estatal Issemym, Toluca, Estado de México, Mexico
| | - E Ruíz-García
- Instituto Nacional de Cancerología, Mexico City, Mexico
| | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico
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22
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Kamal A, Elsheaita A, Abdelnabi M. Association between direct-acting antiviral agents in hepatitis C virus treatment and hepatocellular carcinoma occurrence and recurrence: The endless debate. World J Clin Cases 2022; 10:1764-1774. [PMID: 35317156 PMCID: PMC8891795 DOI: 10.12998/wjcc.v10.i6.1764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/05/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Since direct-acting antiviral agents (DAAs) have been introduced into hepatitis C virus treatment, the sustained viral response (SVR) rate has significantly increased to more than 95%. Scientific evidence supports the idea that SVR after interferon therapy has beneficial effects related to cirrhosis progression, resulting in a reduction in the incidence of hepatocellular carcinoma (HCC). However, a significant debate exists related to DAA impact on HCC development. We reviewed the current literature highlighting the controversial data related to DAA association with de novo HCC occurrence or recurrence and possible pathophysiology of HCC related to DAAs. After a review of the published literature, we believe that the current evidence does not confirm or repudiate a higher rate of de novo HCC occurrence or recurrence related to DAA therapy. More trials are needed to determine if there is an association between HCC occurrence or recurrence and DAA or if it is related to preexisting liver cirrhosis.
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Affiliation(s)
- Ahmed Kamal
- Internal Medicine Department, Faculty of Medicine Alexandria University, Alexandria 21131, Egypt
| | - Ahmed Elsheaita
- Clinical and Experimental Internal Medicine Department, Medical Research Institute Alexandria University, Alexandria 21561, Egypt
| | - Mahmoud Abdelnabi
- Clinical and Experimental Internal Medicine Department, Medical Research Institute Alexandria University, Alexandria 21561, Egypt
- Internal Medicine Department, Texas Tech University Health Science Center, Lubbock, TX 79430, United States
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23
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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24
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Russo FP, Zanetto A, Pinto E, Battistella S, Penzo B, Burra P, Farinati F. Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand? Int J Mol Sci 2022; 23:500. [PMID: 35008926 PMCID: PMC8745141 DOI: 10.3390/ijms23010500] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.
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Affiliation(s)
| | | | | | | | | | | | - Fabio Farinati
- Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy; (F.P.R.); (A.Z.); (E.P.); (S.B.); (B.P.); (P.B.)
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25
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Rosato V, Ascione A, Nevola R, Fracanzani AL, Piai G, Messina V, Claar E, Coppola C, Fontanella L, Lombardi R, Staiano L, Valente G, Fascione MC, Giorgione C, Mazzocca A, Galiero R, Perillo P, Marrone A, Sasso FC, Adinolfi LE, Rinaldi L. Factors affecting long-term changes of liver stiffness in direct-acting anti-hepatitis C virus therapy: A multicentre prospective study. J Viral Hepat 2022; 29:26-34. [PMID: 34582610 DOI: 10.1111/jvh.13617] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 09/07/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022]
Abstract
The long-term changes of liver stiffness (LS) in patients who achieve viral clearance after direct-acting anti-HCV therapy remain undefined. We conducted a multicentre prospective study to investigate this aspect. Patients with HCV infection treated with DAAs were enrolled from six Italian centres; they underwent clinical, biochemical, ultrasound and transient elastography evaluations before treatment (T0), 12 weeks (SVR12) and 24 months (T24) after the end of therapy. Among the 516 consecutive patients enrolled, 301 had cirrhosis. LS significantly decreased from T0 to SVR (14.3 vs 11.1 kPa, p = .002), with a progressive reduction until T24 (8.7 kPa, p < .001). However, only patients with steatosis and those who developed HCC did not experience a late improvement in LS. Multivariate analysis of baseline and follow-up variables identified steatosis as the only independent predictor of failure of LS improvement (OR 1.802, p = .013). ROC curve analysis of the association of LS with the risk of developing HCC showed that SVR12 ≥14.0 kPa had the highest accuracy (sensitivity 82%, specificity 99%; AUC: 0.774). Multivariate analysis revealed that LS was the only variable independently associated with an increased risk of developing HCC (OR 6.470, p = .035). Achieving an SVR was associated with a progressive, long-term decline of LS, suggesting a late improvement in liver fibrosis, besides the resolution of inflammation. Fatty liver and the development of HCC interfered with late reduction of LS. Patients with an LS ≥14 kPa at 12 weeks after the end of treatment were at higher risk for developing HCC.
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Affiliation(s)
| | - Antonio Ascione
- Center for Liver Disease, Ospedale Buon Consiglio - Fatebenefratelli, Napoli, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Guido Piai
- Liver Unit for Transplant Management (SATTE), AORN Sant'Anna e San Sebastiano, Caserta, Italy
| | - Vincenzo Messina
- Infectious Diseases Unit, AORN Sant'Anna e San Sebastiano, Caserta, Italy
| | - Ernesto Claar
- Liver Unit, Ospedale Evangelico Betania, Napoli, Italy
| | - Carmine Coppola
- Internal Medicine and Hepatology Unit, Gragnano Hospital, Gragnano, Italy
| | - Luca Fontanella
- Center for Liver Disease, Ospedale Buon Consiglio - Fatebenefratelli, Napoli, Italy
| | - Rosa Lombardi
- Department of Pathophysiology and Transplantation, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Laura Staiano
- Internal Medicine and Hepatology Unit, Gragnano Hospital, Gragnano, Italy
| | - Giovanna Valente
- Liver Unit for Transplant Management (SATTE), AORN Sant'Anna e San Sebastiano, Caserta, Italy
| | - Maria Chiara Fascione
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Chiara Giorgione
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Annalisa Mazzocca
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | | | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
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26
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Madala S, MacDougall K, Surapaneni BK, Park R, Girotra M, Kasi A. Coinfection of Helicobacter pylori and Hepatitis C Virus in the Development of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. J Clin Med Res 2021; 13:530-540. [PMID: 35059071 PMCID: PMC8734513 DOI: 10.14740/jocmr4637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 11/29/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The relationship between Helicobacter pylori (H. pylori) and hepatocellular carcinoma (HCC) was firstly proposed in 1994 after Ward et al demonstrated the role of Helicobacter hepaticus in the development of HCC in mice. Studies also investigated the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) coexisting with H. pylori in causing HCC. A causal relationship was never confirmed, and the relationship remains controversial. This meta-analysis aimed to summarize the research on this topic and investigate if a relationship exists between H. pylori infection and the development of HCC and if the presence of HCV and HBV along with H. pylori plays a role in liver carcinogenesis. METHODS Following PRISMA guidelines, we performed a systematic review of all relevant studies published in the literature using the keywords "Helicobacter pylori" and "hepatocellular carcinoma" on major literature databases, including PubMed, EMBASE, Web of Science, and Cochrane controlled trials register. A total of 656 research studies were identified between 1994 and 2020. Of those, 26 qualified under our selection criteria. Patients who were positive for HCC were classified as cases and those who did not have HCC were classified as controls. The H. pylori status and HCV status, if available, were identified for both groups. Statistical analysis was carried out by a biostatistician according to the Cochrane reviewer's handbook. RESULTS Out of the 26 studies included in the final analysis, 13 were retrospective case-control studies, 11 were cross-sectional studies, and two were prospective case-control and cohort studies. Overall, the prevalence of H. pylori infection was 64.78% (561 of 866) amongst HCC cases and 47.92% (1,718 of 3,585) in the non-HCC control group. The summary odds ratio (OR) for the association of H. pylori infection with the risk for HCC (using the random-effects model, which accounted for the heterogeneity across the 26 studies) was determined to be 4.75 (95% confidence interval (CI): 3.06 - 7.37, I2 = 63%). We also performed a subgroup analysis to determine the odds of developing HCC in the presence of H. pylori and HCV coinfection. The summary OR of it was 12.76 (95% CI: 4.13 - 39.41, I2 = 78%). The summary OR for the risk of developing HCC in the presence of HCV infection without H. pylori infection was 2.21 (95% CI: 0.70 - 6.94, I2 = 79%). Whereas, the odds of developing HCC in the presence of only H. pylori infection without HCV was found to be 0.54 (95% CI: 0.11 - 2.63, I2 = 80%). There was inconsistency in the data presented in some studies regarding HCV infection status. Since data were extracted from different study designs, subgroup analysis by study design was performed which showed no significant difference between the study groups (P = 0.5705). CONCLUSION This meta-analysis demonstrates a positive association between H. pylori infection and the development of HCC. There is a significantly higher risk of developing HCC in the presence of HCV infection along with H. pylori. Further prospective cohort studies are needed to prove the causal relationship, especially in cases of HBV and HCV coinfection, and cirrhotic patients.
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Affiliation(s)
- Samragnyi Madala
- Department of Geriatric Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Kira MacDougall
- Division of Medical Oncology, University of Oklahoma, Norman, OK, USA
| | | | - Robin Park
- Department of Internal Medicine, MetroWest Medical Center, Framingham, MA, USA
| | - Mohit Girotra
- Division of Gastroenterology and Therapeutic Endoscopy, Swedish Medical Center, Seattle, WA, USA
| | - Anup Kasi
- Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA
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27
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Isfordink CJ, Maan R, de Man RA, van Erpecum KJ, van der Meer AJ. Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection? Eur J Intern Med 2021; 94:6-14. [PMID: 34563447 DOI: 10.1016/j.ejim.2021.08.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/02/2021] [Accepted: 08/27/2021] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) and variceal bleeding are among the most common causes of liver-related mortality in patients with hepatitis C virus (HCV)-induced cirrhosis. Current guidelines recommend HCC and gastroesophageal varices (GEV) surveillance in patients with HCV infection and cirrhosis. However, since the recent introduction of direct-acting antivirals, most patients with cirrhosis are now cured of their chronic HCV infection. As virological cure is considered to substantially reduce the risk of cirrhosis-related complications, this review discusses the current literature concerning the surveillance of HCC and GEV in patients with HCV-induced cirrhosis with a focus on the setting following sustained virological response.
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Affiliation(s)
- Cas J Isfordink
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands; Division of Infectious Diseases, Amsterdam Infection & Immunity Institute Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Raoel Maan
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
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28
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Sánchez-Azofra M, Fernández I, García-Buey ML, Domínguez-Domínguez L, Fernández-Rodríguez CM, Mancebo A, Bonet L, Ryan P, Gea F, Díaz-Sánchez A, García-Mayor M, Martín-Carbonero L, Castillo P, Manzano ML, González-Moreno L, Pulido F, Gutiérrez ML, Moreno JM, García-Amengual IM, Cuevas G, Guerrero A, Rivero-Fernández M, Portales ME, Montes ML, Olveira A. Hepatocellular carcinoma risk in hepatitis C stage-3 fibrosis after sustained virological response with direct-acting antivirals. Liver Int 2021; 41:2885-2891. [PMID: 34392590 DOI: 10.1111/liv.15032] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 07/04/2021] [Accepted: 08/11/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Patients with chronic hepatitis C and stage 3 fibrosis are thought to remain at risk of hepatocellular carcinoma after sustained virological response. We investigated this risk in a large cohort of patients with well-defined stage 3 fibrosis. METHODS We performed a multicentre, ambispective, observational study of chronic hepatitis C patients with sustained virological response after treatment with direct-acting antivirals started between January and December 2015. Baseline stage 3 was defined in a two-step procedure: we selected patients with transient elastography values of 9.5-14.5 kPa and subsequently excluded those with nodular liver surface, splenomegaly, ascites or collaterals on imaging, thrombopenia or esophago-gastric varices. Patients were screened twice-yearly using ultrasound. RESULTS The final sample comprised 506 patients (median age, 57.4 years; males, 59.9%; diabetes, 17.2%; overweight, 44.1%; genotype 3, 8.9%; HIV coinfection, 18.4%; altered liver values, 15.2%). Median follow-up was 33.7 (22.1-39.1) months. Five hepatocellular carcinomas and 1 cholangiocarcinoma were detected after a median of 29.4 months (95% CI: 26.8-39.3), with an incidence of 0.47/100 patients/year (95% CI: 0.17-1.01). In the multivariate analysis, only males older than 55 years had a significant higher risk (hazard ratio 7.2 [95% CI: 1.2-41.7; P = .029]) with an incidence of 1.1/100 patients/year (95% CI: 0.3-2.8). CONCLUSIONS In a large, well-defined cohort of patients with baseline hepatitis C stage-3 fibrosis, the incidence of primary liver tumours was low after sustained virological response and far from the threshold for cost-effectiveness of screening, except in males older than 55 years.
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Affiliation(s)
| | | | | | - Lourdes Domínguez-Domínguez
- HIV Unit, Internal Medicine Department, 12 de Octubre University Hospital, Madrid, Spain.,Instituto de Investigación Sanitaria Hospital, Madrid, Spain
| | | | - Antonio Mancebo
- Gastroenterology Department, Albacete University Hospital, Albacete, Spain
| | - Lucía Bonet
- Gastroenterology Department, Son Espases University Hospital, Palma de Mallorca, Spain
| | - Pablo Ryan
- HIV Unit, Internal Medicine Department, Infanta Leonor University Hospital, Madrid, Spain
| | - Francisco Gea
- Gastroenterology Department, Ramón y Cajal University Hospital, Madrid, Spain
| | - Antonio Díaz-Sánchez
- Gastroenterology Department, Sureste University Hospital, Arganda del Rey, Spain
| | - Marian García-Mayor
- Gastroenterology Department, Hospital Central de la Defensa Gómez Ulla, Madrid, Spain
| | - Luz Martín-Carbonero
- HIV Unit, Internal Medicine Department, La Paz University Hospital, Madrid, Spain
| | - Pilar Castillo
- Gastroenterology Department, La Paz University Hospital, Madrid, Spain
| | - María L Manzano
- Gastroenterology Department, 12 de Octubre University Hospital, Madrid, Spain
| | | | - Federico Pulido
- HIV Unit, Internal Medicine Department, 12 de Octubre University Hospital, Madrid, Spain.,Instituto de Investigación Sanitaria Hospital, Madrid, Spain
| | - María L Gutiérrez
- Gastroenterology Department, Hospital Universitario Fundación Alcorcón, University Rey Juan Carlos, Madrid, Spain
| | - José M Moreno
- Gastroenterology Department, Albacete University Hospital, Albacete, Spain
| | | | - Guillermo Cuevas
- HIV Unit, Internal Medicine Department, Infanta Leonor University Hospital, Madrid, Spain
| | - Antonio Guerrero
- Gastroenterology Department, Ramón y Cajal University Hospital, Madrid, Spain
| | | | - María E Portales
- Gastroenterology Department, Hospital Central de la Defensa Gómez Ulla, Madrid, Spain
| | - María L Montes
- HIV Unit, Internal Medicine Department, La Paz University Hospital, Madrid, Spain
| | - Antonio Olveira
- Gastroenterology Department, La Paz University Hospital, Madrid, Spain
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29
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Valenti L, Pelusi S, Aghemo A, Gritti S, Pasulo L, Bianco C, Iegri C, Cologni G, Degasperi E, D'Ambrosio R, Del Poggio P, Soria A, Puoti M, Carderi I, Pigozzi MG, Carriero C, Spinetti A, Zuccaro V, Memoli M, Giorgini A, Viganò M, Rumi MG, Re T, Spinelli O, Colombo MC, Quirino T, Menzaghi B, Lorini G, Pan A, D'Arminio Monforte A, Buscarini E, Autolitano A, Bonfanti P, Terreni N, Aimo G, Mendeni M, Prati D, Lampertico P, Colombo M, Fagiuoli S. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study. Hepatol Commun 2021; 6:867-877. [PMID: 34811949 PMCID: PMC8948549 DOI: 10.1002/hep4.1851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real‐life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE‐Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow‐up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03‐1.09) and diabetes (OR 2.01 [1.65‐2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35‐0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20‐3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16‐6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11‐0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi‐disciplinary management approach may improve cardiovascular and possibly liver‐related outcomes.
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Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Alessio Aghemo
- Department of Internal Medicine and Hepatology, Humanitas University and Research Hospital, Rozzano, Italy
| | - Sara Gritti
- Fondazione Ricerca Ospedale di Bergamo, Papa Giovanni Hospital, Bergamo, Italy
| | - Luisa Pasulo
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
| | - Cristiana Bianco
- Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Claudia Iegri
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
| | - Giuliana Cologni
- Department of Internal Medicine, Papa Giovanni Hospital, Bergamo, Italy
| | - Elisabetta Degasperi
- Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Roberta D'Ambrosio
- Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Paolo Del Poggio
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Zingonia, Italy
| | - Alessandro Soria
- Division of Infectious Diseases, San Gerardo Hospital-ASST Monza, Monza, Italy
| | - Massimo Puoti
- Department of Infectious Diseases, Hepatitis Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | | | | | - Canio Carriero
- Department of Infectious Diseases, Spedali Civili Hospital-ASST Brescia, Brescia, Italy
| | - Angiola Spinetti
- Department of Infectious Diseases, Spedali Civili Hospital-ASST Brescia, Brescia, Italy
| | - Valentina Zuccaro
- Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia, Italy
| | - Massimo Memoli
- Liver Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
| | - Alessia Giorgini
- Department of Gastroenterology and Hepatology, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Mauro Viganò
- Department of Gastroenterology and Hepatology, San Giuseppe Hospital, Milan, Italy
| | - Maria Grazia Rumi
- Department of Gastroenterology and Hepatology, San Giuseppe Hospital, Milan, Italy
| | - Tiziana Re
- Department of Gastroenterology and Hepatology, Legnano Hospital-ASST Milano Ovest, Milan, Italy
| | - Ombretta Spinelli
- Department of Gastroenterology and Hepatology, Lariana Como Hospital, Milan, Italy
| | - Maria Chiara Colombo
- Department of Gastroenterology and Hepatology, Lariana Como Hospital, Milan, Italy
| | - Tiziana Quirino
- Department of Gastroenterology and Hepatology, Busto Arsizio Hospital ASST Valle Olona, Milan, Italy
| | - Barbara Menzaghi
- Department of Gastroenterology and Hepatology, Busto Arsizio Hospital ASST Valle Olona, Milan, Italy
| | - Gianpaolo Lorini
- Department of Gastroenterology and Hepatology, ASST Franciacorta, Milan, Italy
| | - Angelo Pan
- Department of Internal Medicine, Ospedale di Cremona, Cremona, Italy
| | | | | | | | - Paolo Bonfanti
- Division of Infectious Diseases, ASST Lecco, Lecco, Italy
| | | | | | | | - Daniele Prati
- Precision Medicine Lab, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Pietro Lampertico
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.,Division of Gastroenterology & Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milano, Italy.,CRC "AM. and A. Migliavacca" Center for Liver Disease, Università degli Studi di Milano, Milano, Italy
| | - Massimo Colombo
- Liver Center, San Raffaele Scientific Institute IRCCS, Milano, Italy
| | - Stefano Fagiuoli
- Department of Gastroenterology and Hepatology, Papa Giovanni Hospital, Bergamo, Italy
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30
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Delgado Martínez C, Gómez-Rubio M, Gómez-Domínguez C. Is hepatitis C direct-acting antiviral therapy a risk factor for the development and recurrence of hepatocellular carcinoma? Narrative literature review and clinical practice recommendations. Ann Hepatol 2021; 21:100225. [PMID: 32687878 DOI: 10.1016/j.aohep.2020.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/26/2020] [Accepted: 05/31/2020] [Indexed: 02/04/2023]
Abstract
The development of direct-acting antivirals (DAAs) has been a turning point in chronic hepatitis C treatment. With an efficacy rate on viral eradication close to 100% and an excellent safety profile, they have replaced interferon-based treatments as first-line therapy for hepatitis C virus (HCV). Following the encouraging results observed during the first years with these treatments, new publications suggested an unexpectedly high incidence of hepatocellular carcinoma (HCC) in patients previously treated with DAAs as well as a higher HCC recurrence rate in them. The possible interaction between DAAs and HCC and its impact on HCC incidence and recurrence still remains controversial. The aim of the present work is to review the current state of the matter by analyzing studies that evaluate the association between chronic hepatitis C treatment with DAAs and the development of HCC either de novo or as a recurrence. Following this, clinical practice recommendations are done.
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Affiliation(s)
| | - Mariano Gómez-Rubio
- Division of Digestive Diseases, Hospital Universitario de Getafe, Madrid, Spain; Universidad Europea de Madrid, Madrid, Spain.
| | - Cecilia Gómez-Domínguez
- Division of Digestive Diseases, Hospital Universitario de Getafe, Madrid, Spain; Universidad Europea de Madrid, Madrid, Spain.
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31
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Alqahtani SA, Colombo M. Treatment for Viral Hepatitis as Secondary Prevention for Hepatocellular Carcinoma. Cells 2021; 10:3091. [PMID: 34831314 PMCID: PMC8619578 DOI: 10.3390/cells10113091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with either hepatitis B or C virus (HBV or HCV) are among the most common risk factors for developing hepatocellular carcinoma (HCC). The hepatocarcinogenic potential of these viruses is mediated through a wide range of mechanisms, including the induction of chronic inflammation and oxidative stress and the deregulation of cellular pathways by viral proteins. Over the last decade, effective anti-viral agents have made sustained viral suppression or cure a feasible treatment objective for most chronic HBV/HCV patients. Given the tumorigenic potential of HBV/HCV, it is no surprise that obtaining sustained viral suppression or eradication proves to be effective in preventing HCC. This review summarizes the mechanisms by which HCV and HBV exert their hepatocarcinogenic activity and describes in detail the efficacy of anti-HBV and anti-HCV therapies in terms of HCC prevention. Although these treatments significantly reduce the risk for HCC in patients with chronic viral hepatitis, this risk is not eliminated. Therefore, we evaluate potential strategies to improve these outcomes further and address some of the remaining controversies.
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Affiliation(s)
- Saleh A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287, USA
- Liver Transplant Center, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy;
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32
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Mathur K, Mazhar A, Patel M, Dakhoul L, Burney H, Liu H, Nephew L, Chalasani N, deLemos A, Gawrieh S. Changing Trends of Cirrhotic and Noncirrhotic Hepatocellular Carcinoma in the Era of Directly-Acting Antiviral Agents. Clin Transl Gastroenterol 2021; 12:e00420. [PMID: 34730559 PMCID: PMC8568358 DOI: 10.14309/ctg.0000000000000420] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/22/2021] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION The impact of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) on burden of cirrhotic and noncirrhotic hepatocellular carcinoma (HCC) has not been examined. We assessed recent trends in liver disease etiologies of HCC and proportion of noncirrhotic HCC since DAAs introduction. METHODS Clinical characteristics including presence or absence of underlying cirrhosis were collected from 2,623 patients diagnosed with HCC between 2009 and 2019 at 2 large US centers. Logistic regression was performed to investigate the annual trends of HCC due to different liver diseases and proportions of noncirrhotic cases. RESULTS In the DAA era (2014-2019), annual decline in HCV-HCC (odds ratio [OR] = 0.93, 95% confidence interval [CI] 0.88-0.99, P = 0.019), without change in trends of other liver diseases-related HCC, was observed. Annual increase in noncirrhotic HCC (OR 1.13, 95% CI 1.03-1.23, P = 0.009) and decline in cirrhotic HCC (OR 0.89, 95% CI 0.81-0.97, P = 0.009) along with similar trends for HCV-HCC-increase in noncirrhotic cases (OR 1.35, 95% CI 1.08-1.69, P = 0.009) and decrease in cirrhotic cases (OR 0.92, 95% CI 0.86-0.98, P = 0.012)-were observed during the DAA era. Compared with the pre-DAA era, HCC resection rate increased (10.7% vs 14.0%, P = 0.013) whereas liver transplantation rate decreased (15.1% vs 12.0%, P = 0.023) in the DAA era. DISCUSSION Since introduction of DAAs, proportions of cirrhotic HCC have decreased, whereas proportions of noncirrhotic HCC have increased. These new trends were associated with change in utilization of liver resection and transplantation for HCC. The impact of changing patterns of DAA use on these trends will require further study.
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Affiliation(s)
- Karan Mathur
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
| | - Areej Mazhar
- Department of Medicine, Atrium Health, Charlotte, North Carolina, USA;
| | - Milin Patel
- Department of Medicine, Atrium Health, Charlotte, North Carolina, USA;
| | - Lara Dakhoul
- Department of Gastroenterology & Hepatology, Roudebush VA Medical Center, Indianapolis, Indiana, USA;
| | - Heather Burney
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA.
| | - Hao Liu
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA.
| | - Lauren Nephew
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
| | - Naga Chalasani
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
| | - Andrew deLemos
- Department of Medicine, Atrium Health, Charlotte, North Carolina, USA;
| | - Samer Gawrieh
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
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33
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Knop V, Hoppe D, Vermehren J, Troetschler S, Herrmann E, Vermehren A, Friedrich-Rust M, Sarrazin C, Trebicka J, Zeuzem S, Welker MW. Non-invasive assessment of fibrosis regression and portal hypertension in patients with advanced chronic hepatitis C virus (HCV)-associated liver disease and sustained virologic response (SVR): 3 years follow-up of a prospective longitudinal study. J Viral Hepat 2021; 28:1604-1613. [PMID: 34342081 DOI: 10.1111/jvh.13587] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 12/14/2022]
Abstract
Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1-75) kPa] and EOT [21.3(6.7-73.5) kPa; p < .0001] and EOT and FU144 [16(4.1-75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2-4.1) m/s] and FU144 [1.7(0.9-4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
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Affiliation(s)
- Viola Knop
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Daniel Hoppe
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,St. Elisabeth-Krankenhaus, Leipzig, Germany
| | - Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Sven Troetschler
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,Ketteler Krankenhaus, Offenbach, Germany
| | - Eva Herrmann
- Institut für Biostatistik und mathematische Modellierung, Goethe-Universität Frankfurt, Frankfurt am Main, Germany
| | - Annika Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | | | - Christoph Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,St-Josefs-Hospital, Wiesbaden, Germany
| | - Jonel Trebicka
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Martin-Walter Welker
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
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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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Flisiak R, Zarębska-Michaluk D, Janczewska E, Łapiński T, Rogalska M, Karpińska E, Mikuła T, Bolewska B, Białkowska J, Flejscher-Stępniewska K, Tomasiewicz K, Karwowska K, Pazgan-Simon M, Piekarska A, Berak H, Tronina O, Garlicki A, Jaroszewicz J. Five-Year Follow-Up of Cured HCV Patients under Real-World Interferon-Free Therapy. Cancers (Basel) 2021; 13:3694. [PMID: 34359594 PMCID: PMC8345092 DOI: 10.3390/cancers13153694] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 12/11/2022] Open
Abstract
(1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2-3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver.
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Affiliation(s)
- Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-540 Bialystok, Poland;
| | | | - Ewa Janczewska
- Department of Basic Medical Sciences, Faculty of Health Sciences in Bytom, Medical University of Silesia, 41-902 Bytom, Poland;
| | - Tadeusz Łapiński
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-540 Bialystok, Poland;
| | - Magdalena Rogalska
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-540 Bialystok, Poland;
| | - Ewa Karpińska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, 70-204 Szczecin, Poland;
| | - Tomasz Mikuła
- Department of Infectious and Tropical Disease and Hepatology, Medical University of Warsaw, 02-091 Warsaw, Poland;
| | - Beata Bolewska
- Department of Infectious Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Jolanta Białkowska
- Department of Infectious and Liver Diseases, Medical University of Lodz, 90-419 Lodz, Poland;
| | - Katarzyna Flejscher-Stępniewska
- Department of Infectious Diseases, Liver Diseases and Immune Deficiencies, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Krzysztof Tomasiewicz
- Department of Infectious Diseases and Hepatology, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Kornelia Karwowska
- Department of Infectious Diseases and Hepatology, Collegium Medicum, Nicolaus Copernicus University, 87-030 Bydgoszcz, Poland;
| | - Monika Pazgan-Simon
- Department of Infectious Diseases and Hepatology, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Lodz, 90-419 Lodz, Poland;
| | - Hanna Berak
- Daily Unit, Hospital of Infectious Diseases in Warsaw, 01-201 Warsaw, Poland;
| | - Olga Tronina
- Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland;
| | - Aleksander Garlicki
- Department of Infectious and Tropical Diseases, Jagiellonian University Medical College, 31-008 Krakow, Poland;
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, 40-055 Katowice, Poland;
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36
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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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Brozzetti S, Tancredi M, Bini S, De Lucia C, Antimi J, D’Alterio C, De Sanctis GM, Furlan C, Malpassuti VC, Lucatelli P, Di Martino M, Bezzi M, Ciardi A, Pascale RM. HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly. Cancers (Basel) 2021; 13:3025. [PMID: 34204186 PMCID: PMC8235445 DOI: 10.3390/cancers13123025] [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: 04/29/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: "de novo occurrent HCC", "recurrent HCC", and "without HCC". Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: "de novo occurrent'' 18.13% and "recurrent'' 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% "de novo occurrent" HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies.
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Affiliation(s)
- Stefania Brozzetti
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Marsia Tancredi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Simone Bini
- Department of Translational and Precision Medicine, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy
| | - Chiara De Lucia
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Jessica Antimi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Chiara D’Alterio
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Giuseppe Maria De Sanctis
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | - Caterina Furlan
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | | | - Pierleone Lucatelli
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Michele Di Martino
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Mario Bezzi
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | - Rosa Maria Pascale
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy;
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Nevola R, Rinaldi L, Zeni L, Romano C, Marrone A, Galiero R, Pafundi PC, Acierno C, Vetrano E, Adinolfi LE. Changes in clinical scenarios, management, and perspectives of patients with chronic hepatitis C after viral clearance by direct-acting antivirals. Expert Rev Gastroenterol Hepatol 2021; 15:643-656. [PMID: 33445990 DOI: 10.1080/17474124.2021.1877136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients. AREAS COVERED The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses. EXPERT OPINION Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.
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Affiliation(s)
- Riccardo Nevola
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Rinaldi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Letizia Zeni
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ciro Romano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Aldo Marrone
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Raffaele Galiero
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pia Clara Pafundi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carlo Acierno
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erica Vetrano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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Jayaswal ANA, Levick C, Collier J, Tunnicliffe EM, Kelly MD, Neubauer S, Barnes E, Pavlides M. Liver cT 1 decreases following direct-acting antiviral therapy in patients with chronic hepatitis C virus. Abdom Radiol (NY) 2021; 46:1947-1957. [PMID: 33247768 PMCID: PMC8131342 DOI: 10.1007/s00261-020-02860-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/04/2020] [Accepted: 11/07/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Direct-acting antiviral therapies (DAAs) for treatment of chronic hepatitis C virus (HCV) have excellent rates of viral eradication, but their effect on regression of liver fibrosis is unclear. The primary aim was to use magnetic resonance imaging (MRI) and spectroscopy (MRS) to evaluate changes in liver fibrosis, liver fat and liver iron content (LIC) in patients with chronic HCV following treatment with DAAs. METHODS In this prospective study, 15 patients with chronic HCV due to start treatment with DAAs and with transient elastography (TE) > 8 kPa were recruited consecutively. Patients underwent MRI and MRS at baseline (before treatment), and at 24 weeks and 48 weeks after the end of treatment (EoT) for the measurement of liver cT1 (fibroinflammation), liver fat and T2* (LIC). RESULTS All patients achieved a sustained virological response. Liver cT1 showed significant decreases from baseline to 24 weeks post EoT (876 vs 806 ms, p = 0.002, n = 15), baseline to 48 weeks post EoT (876 vs 788 ms, p = 0.0002, n = 13) and 24 weeks post EoT to 48 weeks post EoT (806 vs 788 ms, p = 0.016, n = 13). Between baseline and 48 weeks EoT significant reduction in liver fat (5.17% vs 2.65%, p = 0.027) and an increase in reported LIC (0.913 vs 0.950 mg/g, p = 0.021) was observed. CONCLUSION Liver cT1 decreases in patients with chronic HCV undergoing successful DAA treatment. The relatively fast reduction in cT1 suggests a reduction in inflammation rather than regression of fibrosis.
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Affiliation(s)
- Arjun N A Jayaswal
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Christina Levick
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Jane Collier
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Elizabeth M Tunnicliffe
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Oxford, UK
| | | | - Stefan Neubauer
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Oxford, UK
| | - Eleanor Barnes
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Oxford, UK
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - Michael Pavlides
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
- Oxford NIHR Biomedical Research Centre, Oxford, UK.
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40
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Sahakyan Y, Lee-Kim V, Bremner KE, Bielecki JM, Krahn MD. Impact of direct-acting antiviral regimens on mortality and morbidity outcomes in patients with chronic hepatitis c: Systematic review and meta-analysis. J Viral Hepat 2021; 28:739-754. [PMID: 33556225 DOI: 10.1111/jvh.13482] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/23/2021] [Indexed: 02/06/2023]
Abstract
The long-term effects of direct-acting antiviral therapies (DAAs) for chronic hepatitis C (CHC) remain uncertain. The objective of this systematic review and meta-analysis was to assess the impact of DAAs on CHC progression and mortality. We searched Ovid MEDLINE, Ovid EMBASE and PubMed databases (January 2011 to March 2020) for studies that compared the efficacy of DAAs to a non-DAA control in patients with CHC. Main outcomes were the adjusted hazard ratios (HRs) for mortality, liver decompensation, HCC occurrence and recurrence. Pooled estimates of HRs were determined using random-effects meta-analyses with inverse variance weighting, with sensitivity analyses and meta-regression to explore the effects of clinical factors. We identified 39 articles for the primary analysis. Compared with unexposed individuals, patients treated with DAA had a reduced risk of death (HR; CI = 0.44; 0.38-0.52), decompensation (HR; CI = 0.54; 0.38- 0.76) and HCC occurrence (HR; CI = 0.72; 0.61- 0.86). The protective effect of DAA on HCC recurrence was less clear (HR; CI = 0.72; 0.44-1.16). Sustained virologic response (SVR) attainment was a significant predictor of reduced mortality (HR; CI = 0.33; 0.23-0.46), decompensation (HR; CI = 0.11; 0.05-0.24), HCC occurrence (HR; CI = 0.31; 0.27-0.37) and HCC recurrence (HR; CI = 0.32; 0.20-0.51). Meta-regression showed no evidence of effect modification by patient age, sex, presence of cirrhosis or length of follow-up. In conclusion, our findings show protective effects of DAA treatment and DAA-related SVR on CHC progression and mortality.
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Affiliation(s)
- Yeva Sahakyan
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Victoria Lee-Kim
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.,School of Medicine, Queens University, Kingston, ON, Canada
| | - Karen E Bremner
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Joanna M Bielecki
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Murray D Krahn
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, ON, Canada.,Department of Medicine, University of Toronto and University Health Network, Toronto, ON, Canada.,Institute for Clinical Evaluative Sciences (ICES), Toronto, ON, Canada
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41
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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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Kwan BS, Kim JH, Park SJ, Choe WH, Kwon SY, Yoo BC. Comparison of the efficacy and safety of direct-acting antiviral therapy with or without hepatitis C-related hepatocellular carcinoma. Korean J Intern Med 2021; 36:292-304. [PMID: 32241083 PMCID: PMC7969069 DOI: 10.3904/kjim.2019.297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/24/2019] [Accepted: 11/24/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND/AIMS Chronic hepatitis C (CHC) treatment has dramatically improved since direct-acting antiviral (DAA) therapy was introduced. However, the use of DAA therapy in CHC patients with hepatocellular carcinoma (HCC) remains controversial. We investigated the DAA treatment response in CHC patients with HCC. METHODS We retrospectively analyzed CHC patients treated with DAA from 2016 to 2018. Patients were divided into two groups based on their HCC-history before DAA therapy. Baseline characteristics, sustained virologic response at 12 weeks (SVR 12), and HCC recurrence after DAA therapy were evaluated. We also used propensity score matching (PSM) in a 2:1 ratio to reduce confounding variables. RESULTS A total of 192 patients were enrolled; 78.1% were treatment-naïve, and 34.9% had liver cirrhosis (LC). Among these patients, 168 did not have HCC, and 24 had HCC. The HCC group was older (57.0 years vs. 72.0 years, p < 0.001), had a higher incidence of LC (26.2% vs. 95.8%, p < 0.001), fibrosis-4 index (2.6 vs. 9.2, p < 0.001), liver stiffness measurement (7.0 kPa vs. 17.4 kPa, p = 0.012), and α-fetoprotein (4.4 ng/mL vs. 8.2 ng/mL, p ≤ 0.001). The SVR 12 rate was 97.0% in the non- HCC group and 91.7% in the HCC group (p = 0.213). HCC recurrence was observed in 14 patients (58.3%) in the HCC group. CONCLUSION DAA treatment efficacy in CHC patients with or those without HCC were not significantly different, and HCC recurrence was relatively common.
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Affiliation(s)
- Byung Soo Kwan
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
| | - Seong Jun Park
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Byung-Chul Yoo
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
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Berumen J, Baglieri J, Kisseleva T, Mekeel K. Liver fibrosis: Pathophysiology and clinical implications. WIREs Mech Dis 2021; 13:e1499. [PMID: 32713091 PMCID: PMC9479486 DOI: 10.1002/wsbm.1499] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/30/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a clinically significant finding that has major impacts on patient morbidity and mortality. The mechanism of fibrosis involves many different cellular pathways, but the major cell type involved appears to be hepatic stellate cells. Many liver diseases, including Hepatitis B, C, and fatty liver disease cause ongoing hepatocellular damage leading to liver fibrosis. No matter the cause of liver disease, liver-related mortality increases exponentially with increasing fibrosis. The progression to cirrhosis brings more dramatic mortality and higher incidence of hepatocellular carcinoma. Fibrosis can also affect outcomes following liver transplantation in adult and pediatric patients and require retransplantation. Drugs exist to treat Hepatitis B and C that reverse fibrosis in patients with those viral diseases, but there are currently no therapies to directly treat liver fibrosis. Several mouse models of chronic liver diseases have been successfully reversed using novel drug targets with current therapies focusing mostly on prevention of myofibroblast activation. Further research in these areas could lead to development of drugs to treat fibrosis, which will have invaluable impact on patient survival. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
| | - Jacopo Baglieri
- Department of Surgery, University of California, San Diego
- Department of Medicine, University of California, San Diego
| | | | - Kristin Mekeel
- Department of Surgery, University of California, San Diego
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Degasperi E, Galmozzi E, Pelusi S, D'Ambrosio R, Soffredini R, Borghi M, Perbellini R, Facchetti F, Iavarone M, Sangiovanni A, Valenti L, Lampertico P. Hepatic Fat-Genetic Risk Score Predicts Hepatocellular Carcinoma in Patients With Cirrhotic HCV Treated With DAAs. Hepatology 2020; 72:1912-1923. [PMID: 32762045 DOI: 10.1002/hep.31500] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/28/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Genetic factors and steatosis predispose to hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus; however, their impact in patients with cirrhosis cured by direct-acting antivirals (DAAs) is still undefined. We assessed the association between a genetic risk score (GRS) of hepatic fat accumulation, combining variants in PNPLA3 (patatin-like phospholipase domain containing 3), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TM6SF2 (transmembrane 6 superfamily member 2), GCKR (glucokinase regulator), and HCC in patients treated with DAAs. APPROACH AND RESULTS We considered 509 consecutive patients with HCV cirrhosis (defined histologically or when liver stiffness ≥12 kPa) treated with DAAs. HCC was diagnosed according to international recommendations. GRS was calculated from the weighted impact of single variants on hepatic fat content quantified by H1 spectrometry in the general population (Dallas Heart Study). During a median follow-up of 43 (3-57) months after DAA start, 36 of 452 (8%) patients developed de novo HCC, 4-year cumulative probability being 9% (95% confidence interval 7%-12%). Male sex (hazard ratio [HR] 2.54, P = 0.02), diabetes (HR 2.39, P = 0.01), albumin (HR 0.35, P = 0.001), and GRS score >0.597 (HR 2.30, P = 0.04) were independent predictors of de novo HCC. In contrast, single genetic risk variants were not useful in stratifying HCC risk. The proportion of patients who developed HCC according to the combination of the independent risk factors ranged from 11% to 67%. HCC recurred in 28 of 57 (49%) patients with previous history; diabetes and ethnicity were the only independent predictors of HCC recurrence. CONCLUSIONS In a large cohort of DAA-treated patients with cirrhotic HCV, GRS was associated with de novo HCC independently of classical risk factors, including liver disease severity. These data suggest that hepatic fat (i.e., lipotoxicity) promotes HCC in this setting and may represent a target for chemoprevention. Combination of clinical and genetic predictors may improve HCC risk stratification.
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Affiliation(s)
- Elisabetta Degasperi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Enrico Galmozzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Serena Pelusi
- Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Roberta D'Ambrosio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Roberta Soffredini
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Marta Borghi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Riccardo Perbellini
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Floriana Facchetti
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Massimo Iavarone
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Angelo Sangiovanni
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Luca Valenti
- Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Perceptions of network based recruitment for hepatitis C testing and treatment among persons who inject drugs: a qualitative exploration. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2020; 88:103019. [PMID: 33160152 DOI: 10.1016/j.drugpo.2020.103019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/30/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Social network interventions that take advantage of existing individual and group relationships may help overcome the significant patient, provider, and system level barriers that contribute to low hepatitis C Virus (HCV) treatment uptake among people who inject drugs (PWID). METHODS We conducted semi-structured interviews with 20 HCV antibody positive PWID (15 male, 5 female) in Baltimore, Maryland, USA. We utilized thematic analysis and employed both inductive and deductive coding techniques to assess perceptions of barriers and facilitators of social network interventions for HCV testing, linkage to care, and treatment among PWID. RESULTS PWID perceived a high prevalence of HCV within their social networks, especially within injection drug use networks. Overwhelmingly, participants reported a willingness to discuss HCV and provide informational, instrumental, and emotional support to their network members. Support included sharing knowledge, such as where and how to access HCV care, as well as sharing lived experiences about HCV treatment that could help peers build trust within networks. Participants who were already linked into HCV care had an increased understanding of using social network interventions to provide peer navigation, by accompanying network members to HCV related appointments. Across interviews, drug use related stigma and feeling undeserving of HCV treatment due to previous negative experiences accessing the health care system emerged as a major barrier to linkage to HCV treatment and cure. Undeservingness was often internalized and projected onto network members. To overcome this, participants supported access to low-barrier HCV treatment in alternative locations such as community-based or mobile clinics and drug treatment centers. CONCLUSION Social network based interventions have potential to increase HCV treatment uptake among PWID. To be successful, these interventions will need to train peers to share accurate information and personal experiences with HCV testing and treatment and enhance their ability to provide support to network members who face significant stigma related to both HCV and drug use.
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Mendizabal M, Piñero F, Ridruejo E, Herz Wolff F, Anders M, Reggiardo V, Ameigeiras B, Palazzo A, Alonso C, Schinoni MI, Videla Zuain MG, Tanno F, Figueroa S, Santos L, Peralta M, Soza A, Vistarini C, Adrover R, Fernández N, Perez D, Hernández N, Estepo C, Bruno A, Descalzi V, Sixto M, Borzi S, Cocozzella D, Zerega A, de Araujo A, Varón A, Rubinstein F, Cheinquer H, Silva M. Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-Acting Antiviral Agents. Clin Gastroenterol Hepatol 2020; 18:2554-2563.e3. [PMID: 32113892 DOI: 10.1016/j.cgh.2020.02.044] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/23/2020] [Accepted: 02/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about how a sustained virologic response (SVR) to treatment of hepatitis C virus infection with direct-acting antivirals (DAAs) affects patient mortality and development of new liver-related events. We aimed to evaluate the incidence of disease progression in patients treated with DAAs. METHODS We performed a prospective multicenter cohort study of 1760 patients who received DAA treatment at 23 hospitals in Latin America, from May 1, 2016, through November 21, 2019. We excluded patients with a history of liver decompensation, hepatocellular carcinoma (HCC), or solid-organ transplantation. Disease progression after initiation of DAA therapy included any of the following new events: liver decompensation, HCC, liver transplantation, or death. Evaluation of variables associated with the primary outcome was conducted using a time-dependent Cox proportional hazards models. RESULTS During a median follow-up period of 26.2 months (interquartile range, 15.3-37.5 mo), the overall cumulative incidence of disease progression was 4.1% (95% CI, 3.2%-5.1%), and after SVR assessment was 3.6% (95% CI, 2.7%-4.7%). Baseline variables associated with disease progression were advanced liver fibrosis (hazard ratio [HR], 3.4; 95% CI, 1.2-9.6), clinically significant portal hypertension (HR, 2.1; 95% CI, 1.2-3.8), and level of albumin less than 3.5 mg/dL (HR, 4.1; 95% CI, 2.3-7.6), adjusted for SVR achievement as a time covariable. Attaining an SVR reduced the risk of liver decompensation (HR, 0.3; 95% CI, 0.1-0.8; P = .016) and de novo HCC (HR, 0.2; 95% CI, 0.1%-0.8%; P = .02) in the overall cohort. CONCLUSIONS Treatment of hepatitis C virus infection with DAAs significantly reduces the risk of new liver-related complications and should be offered to all patients, regardless of disease stage. Clinicaltrials.gov: NCT03775798.
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Affiliation(s)
- Manuel Mendizabal
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina.
| | - Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina
| | - Ezequiel Ridruejo
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina; Centro de Educación Médica e Investigaciones Clínicas, CEMIC, Ciudad de Buenos Aires, Argentina
| | | | | | | | | | | | - Cristina Alonso
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina
| | | | | | | | | | | | - Mirta Peralta
- Hospital Francisco J. Muñiz, Ciudad de Buenos Aires, Argentina
| | - Alejandro Soza
- Hospital Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | | | | | | | | | - Claudio Estepo
- Hospital Cosme Argerich, Ciudad de Buenos Aires, Argentina
| | - Andres Bruno
- Hospital Cosme Argerich, Ciudad de Buenos Aires, Argentina
| | | | | | | | | | | | | | - Adriana Varón
- Hospital Francisco J. Muñiz, Ciudad de Buenos Aires, Argentina
| | | | - Hugo Cheinquer
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Marcelo Silva
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina
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Piñero F, Tanno M, Aballay Soteras G, Tisi Baña M, Dirchwolf M, Fassio E, Ruf A, Mengarelli S, Borzi S, Fernández N, Ridruejo E, Descalzi V, Anders M, Mazzolini G, Reggiardo V, Marciano S, Perazzo F, Spina JC, McCormack L, Maraschio M, Lagues C, Gadano A, Villamil F, Silva M, Cairo F, Ameigeiras B. Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma. Ann Hepatol 2020; 19:546-569. [PMID: 32593747 DOI: 10.1016/j.aohep.2020.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/05/2020] [Accepted: 06/10/2020] [Indexed: 02/08/2023]
Abstract
The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina.
| | - Mario Tanno
- Hospital Centenario de Rosario, Santa Fe, Argentina
| | | | - Matías Tisi Baña
- Internal Medicine and Epidemiology Department, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Andrés Ruf
- Hospital Privado de Rosario, Santa Fe, Argentina
| | | | - Silvia Borzi
- Instituto Rossi, La Plata, Buenos Aires, Argentina
| | | | - Ezequiel Ridruejo
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina; Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Ciudad de Buenos Aires, Argentina
| | | | | | - Guillermo Mazzolini
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | | | | | | | | | - Cecilia Lagues
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
| | | | | | - Marcelo Silva
- Hepatology and Liver Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629HJ Buenos Aires, Argentina
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Kumada T, Toyoda H, Yasuda S, Tada T, Ogawa S, Takeshima K, Tanaka J, Chayama K, Johnson PJ. Impact of the introduction of direct-acting anti-viral drugs on hepatocarcinogenesis: a prospective serial follow-up MRI study. Aliment Pharmacol Ther 2020; 52:359-370. [PMID: 32519782 DOI: 10.1111/apt.15825] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 04/17/2020] [Accepted: 05/10/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND We conducted a prospective study using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) to determine whether sustained virological response (SVR) by direct-acting anti-viral (DAA) drugs suppresses hepatocarcinogenesis in patients with hepatitis C virus (HCV) infection. AIM To use serial Gd-EOB-MRI to assess the impact of DAAs on hepatocarcinogenesis. METHODS Between February 2008 and December 2018, 1083 consecutive patients with HCV infection underwent Gd-EOB-MRI. Of these, 719 patients were enrolled, including 210 patients in the 'Non-DAA group', who did not receive DAAs before the introduction of DAAs, and 509 patients in the 'DAA group', who achieved SVR after the introduction of DDAs. Factors associated with hepatocarcinogenesis were analysed by a Cox proportional hazard model. In addition, hepatocarcinogenesis was classified into two types, 'multistep' and 'de novo', on the basis of Gd-EOB-MRI findings. Factors associated with each type were analysed by Fine and Gray proportional hazards models. RESULTS Hepatocarcinogenesis was observed in 67 of 719 (9.3%) patients. Factors associated with hepatocarcinogenesis were male gender, albumin-bilirubin (ALBI) grade 2 or 3, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) ≥5%, the presence of nonhypervascular hypointense nodules (NHHNs) and Non-DAA group. Of 67 patients, multistep hepatocarcinogenesis occurred in 58 patients (86.6%) and de novo hepatocarcinogenesis occurred in nine patients (13.4%). Factors associated with multistep hepatocarcinogenesis were male gender and Non-DAA group. CONCLUSION The eradication of HCV by DAA therapy reduces multistep hepatocarcinogenesis.
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Affiliation(s)
- Takashi Kumada
- Department of Nursing, Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Sadanobu Ogawa
- Department of Imaging Diagnosis, Ogaki Municipal Hospital, Ogaki, Japan
| | - Kenji Takeshima
- Department of Imaging Diagnosis, Ogaki Municipal Hospital, Ogaki, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima, Japan
| | - Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
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Rinaldi L, Nevola R, Franci G, Perrella A, Corvino G, Marrone A, Berretta M, Morone MV, Galdiero M, Giordano M, Adinolfi LE, Sasso FC. Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics. Cancers (Basel) 2020; 12:1351. [PMID: 32466400 PMCID: PMC7352473 DOI: 10.3390/cancers12061351] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 02/05/2023] Open
Abstract
Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short-medium term but reduces the risk of HCC in the medium-long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects' post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Gianluigi Franci
- Department of Medicine, Surgery, Dentistry, University of Salerno “Scuola Medica Salernitana”, 84100 Salerno, Italy;
| | - Alessandro Perrella
- Immunological and Neurological Infectious Diseases, Cotugno Hospital, 80100 Naples, Italy;
| | - Giusy Corvino
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.C.); (M.V.M.); (M.G.)
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Massimiliano Berretta
- Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, 33081 Aviano, Italy;
| | - Maria Vittoria Morone
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.C.); (M.V.M.); (M.G.)
| | - Marilena Galdiero
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.C.); (M.V.M.); (M.G.)
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
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