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1
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El-Serag HB, Duong H, Luster M, Kanwal F, Hill DD, Burroughs M, Hernandez C, Haber BA, Larsen LM, Marcinak JF, Wegrzyn LR, Kramer JR. Risk of Hepatocellular Cancer in U.S. Patients With Compensated Cirrhosis Treated With Direct-Acting Antivirals Versus Interferon. Aliment Pharmacol Ther 2025; 61:1226-1237. [PMID: 39921230 DOI: 10.1111/apt.18525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/07/2024] [Accepted: 01/18/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Few studies have examined the risk of de novo hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-infected patients with cirrhosis who received interferon (IFN)-free direct-acting antiviral (DAA) therapy relative to patients who received IFN-containing therapy or remained untreated. AIMS To estimate the risk of de novo HCC with DAA treatment in cirrhotic HCV patients compared to no anti-HCV treatment and those treated with IFN-based therapy. METHODS We identified patients with chronic HCV infection and compensated cirrhosis in the US Department of Veterans Affairs healthcare system treated with IFN (2005 to 2013) or DAAs (2013 to 2017). We compared the risk of de novo HCC for patients treated with DAAs, IFN-containing regimens or no treatment after accounting for differences in demographics, alcohol and drug abuse, comorbidities, laboratory values, healthcare utilisation, prior HCV treatment and HCC surveillance. RESULTS A total of 53,847 patients contributed to untreated time, 27,147 patients contributed to DAA-treated time (15,641 contributed to both untreated and DAA-treated times) and 6809 patients contributed to IFN-treated time. HCC risk associated with DAA treatment was significantly lower than untreated [adjusted HR: 0.70 (95% CI: 0.65-0.74)]. The risk of HCC was not significantly different for patients treated with DAA compared with those treated with IFN [adjusted HR: 0.98 (95% CI: 0.87-1.10)]. CONCLUSIONS The study shows a reduced risk of de novo HCC among patients with chronic HCV-related compensated cirrhosis who received DAA treatment compared to that of untreated patients. There were no differences in HCC risk between DAA-treated and IFN-treated patients.
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Affiliation(s)
- Hashem B El-Serag
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Hao Duong
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Michelle Luster
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Fasiha Kanwal
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | | | | | | | | | | | | | | | - Jennifer R Kramer
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
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2
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Ran X, Xu Y, Wang Y, Zeng C, Gong C, Wang N, Cai D. Genotype 3 is linked to worse liver disease progression in hepatitis C patients even after SVR following DAA therapy. Front Cell Infect Microbiol 2025; 15:1510939. [PMID: 39963406 PMCID: PMC11830654 DOI: 10.3389/fcimb.2025.1510939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
Background and aims HCV genotype (GT) 3 is associated with rapid liver disease progression. However, the liver disease progression and its risk factors in patients with HCV GT 3 infection after sustained virological response (SVR) following direct-acting antivirals (DAAs) remain unclear. Therefore, we aimed to investigate the liver disease progression of patients with GT 3 after SVR. Methods This was a retrospective cohort study of patients with HCV infection who achieved SVR by DAAs. The clinical outcome was overall liver disease progression (OLDP), defined as newly diagnosed compensated liver cirrhosis, decompensated liver cirrhosis, or hepatocellular carcinoma. The incidence of OLDP was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the risk factors for OLDP. Results A total of 409 patients (46.9% GT3) were followed for 43.7 (32.9, 58.7) months. The incidence of OLDP was higher in patients with GT 3 (4.63/100PY) than non-GT 3 (0.60/100PY; P < 0.001). According to Cox multivariate analysis, GT 3 was significantly associated with OLDP (HR 6.41, 95% CI 1.82 - 22.56; P=0.004). The predictors of OLDP in patients with GT 3 were HCV recurrence (HR 12.15, 95% CI 3.18 - 46.46; P < 0.001) and FIB-4 > 3.25 (HR 16.40, 95% CI 1.03 - 39.81; P = 0.046) at baseline. Conclusion HCV GT 3-infected patients remain at a higher risk of OLDP even after achieving SVR by DAAs, especially patients with advanced liver fibrosis and at high risk for reinfection or virological late relapse.
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Affiliation(s)
- Xiping Ran
- Department of Gastroenterology, Chonggang General Hospital, Chongqing, China
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yang Xu
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ying Wang
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Cheng Zeng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Chen Gong
- Department of Neurology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ni Wang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Dachuan Cai
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Gujarathi R, Klein JA, Liao CY, Pillai A. The Changing Demographics and Epidemiology of Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:1-15. [PMID: 39608950 DOI: 10.1016/j.cld.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
The epidemiology of hepatocellular carcinoma (HCC) has shifted significantly in the last 2 decades with non-viral etiologies such as metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease on the rise. Key factors include the global obesity epidemic and the resurgence of alcohol use disorder, both of which were exacerbated by the coronavirus disease 2019 pandemic. While these non-viral etiologies of HCC are becoming the leading cause in developed countries, the potential impact of immigration patterns on Hepatitis B virus epidemiology cannot be ignored. The risk of HCC remains significant in individuals with cirrhosis and viral hepatitis after curative treatments.
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Affiliation(s)
- Rushabh Gujarathi
- Department of Internal Medicine, University of Chicago, Chicago, IL, USA
| | - Jeremy A Klein
- Department of Internal Medicine, University of Chicago, Chicago, IL, USA
| | - Chih-Yi Liao
- Department of Internal Medicine, University of Chicago, Chicago, IL, USA
| | - Anjana Pillai
- Department of Internal Medicine, University of Chicago, Chicago, IL, USA.
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4
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Soraya S, Arfianti A, Adikusuma W, Irham LM, Hamidy MY, Winarto W, Rangkuti IF, Darmawi D. Unveiling the impacts of metformin on hepatocellular carcinoma: A bioinformatic exploration in cell lines. NARRA J 2024; 4:e968. [PMID: 39816125 PMCID: PMC11731935 DOI: 10.52225/narra.v4i3.968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/12/2024] [Indexed: 01/18/2025]
Abstract
The most common type of liver cancer is hepatocellular carcinoma (HCC), accounting for 75-85% of cases. Despite its associated side effects, sorafenib remains the standard treatment for HCC. Given the critical need to improve therapeutic efficacy while minimizing adverse effects, alternative drugs must be thoroughly investigated. Numerous studies indicate that combining sorafenib with metformin results in a more favorable treatment profile. The aim of this study was to employ bioinformatics methodologies to elucidate the molecular pathways and genetic underpinnings of metformin's efficacy in HCC treatment. Genes associated with metformin and its action against HCC (Huh-7 and HepG2 cells) were acquired from the NCBI-GEO data collection by utilizing pre-determined keywords. Subsequently, pathways implicated in metformin-mediated HCC treatment were analyzed through the Kyoto Encyclopedia of Genes and Genomes (KEGG). Our analysis revealed the involvement of multiple pathways, with metabolic pathways implicated in 80% of the total cases. Neurodegenerative pathways were involved in only around 60% of the total cases. These findings align with the multifaceted mechanisms of metformin's action, encompassing adenosine monophosphate-activated protein kinase activation, apoptosis induction, insulin regulation, anti-inflammatory responses, and modulation of cell proliferation. This comprehensive investigation sheds light on the intricate molecular landscape underpinning metformin's therapeutic efficacy in HCC, thereby informing potential avenues for optimizing treatment strategies.
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Affiliation(s)
- Soraya Soraya
- Master Program in Biomedical Sciences, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
- Department of Biochemistry, Faculty of Medicine, Universitas Awal Bros, Pekanbaru, Indonesia
| | - Arfianti Arfianti
- Department of Medical Biology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Wirawan Adikusuma
- Department of Pharmacy, Universitas Muhammadiyah Mataram, Mataram, Indonesia
- Research Center for Computing, Research Organization for Electronics and Informatics, National Research and Innovation Agency, Cibinong Science Center, Cibinong, Indonesia
| | - Lalu M. Irham
- Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Indonesia
| | - Muhammad Y. Hamidy
- Department of Pharmacology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Winarto Winarto
- Department of Histology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Ina F. Rangkuti
- Department of Pathological Anatomy, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
| | - Darmawi Darmawi
- Department of Histology, Faculty of Medicine, Universitas Riau, Pekanbaru, Indonesia
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Maekawa S, Takano S, Enomoto N. Risk of hepatocellular carcinoma after viral clearance achieved by DAA treatment. J Formos Med Assoc 2024; 123:1124-1130. [PMID: 38245398 DOI: 10.1016/j.jfma.2024.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/22/2024] Open
Abstract
The advent of direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment, enabling most HCV-infected patients to achieve a sustained viral response (SVR) easily and safely in a short period. On the other hand, it is gradually being recognized that a significant proportion of patients are still at risk of developing de novo and recurrent hepatocellular carcinoma (HCC), even after HCV elimination, and therefore, elucidation of the risk of de novo and recurrent HCC, investigation of its molecular basis, and construction of accurate prediction models are emerging as new important clinical topics. In this review, we present recent advances regarding these issues.
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Affiliation(s)
- Shinya Maekawa
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
| | - Shinichi Takano
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuyuki Enomoto
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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Choi JH, Thung SN. Pathology and diagnostic approaches to well-differentiated hepatocellular lesions: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:5. [PMID: 39442859 PMCID: PMC11812079 DOI: 10.12701/jyms.2024.00766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024]
Abstract
Well-differentiated hepatocellular lesions (WDHLs) are liver tumors or nonneoplastic lesions in which the cells closely resemble normal hepatocytes. These lesions often include focal nodular hyperplasia, hepatocellular adenoma, macroregenerative nodule, dysplastic nodule, and well-differentiated hepatocellular carcinoma. The diagnosis of these lesions remains challenging because of their morphological similarities, particularly when examined using needle biopsy. The accurate diagnosis of WDHLs is crucial for patient management and prognosis. This review addresses the histopathological characteristics and diagnostic approaches of WDHLs.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Iman K, Mirza MU, Sadia F, Froeyen M, Trant JF, Chaudhary SU. Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease. Viruses 2024; 16:1250. [PMID: 39205224 PMCID: PMC11359326 DOI: 10.3390/v16081250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A, including H57R and S139P within the catalytic triad. We then modelled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e., cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A-ligand interaction, resulting in unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A.
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Affiliation(s)
- Kanzal Iman
- Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan; (K.I.); (F.S.)
| | - Muhammad Usman Mirza
- Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada;
| | - Fazila Sadia
- Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan; (K.I.); (F.S.)
| | - Matheus Froeyen
- Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven—University of Leuven, B-3000 Leuven, Belgium;
| | - John F. Trant
- Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada;
| | - Safee Ullah Chaudhary
- Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan; (K.I.); (F.S.)
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8
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Hashmi ZY, Hashmi S, Raza A. Efficacy, safety, and quality of life profile of Genotype-3 Chronic Hepatitis-C Pakistani patients receiving ledipasvir plus sofosbuvir treatment. Pak J Med Sci 2024; 40:1430-1436. [PMID: 39092072 PMCID: PMC11255826 DOI: 10.12669/pjms.40.7.7869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 01/18/2024] [Accepted: 03/26/2024] [Indexed: 08/04/2024] Open
Abstract
Objective This study aimed to assess the overall treatment response of Genotype-3 Chronic HCV Pakistani Patients with or without cirrhosis to Ledipasvir plus Sofosbuvir combination. Method In this observational study, HCV Genotype-3 patients were enrolled from Liver Center, DHQ Hospital, Faisalabad and divided into two groups, i.e., non-cirrhotic and compensated cirrhotic patients. The study spanned for a period of 24 months (November 2019 - November 2021) from the first enrollment to the last follow up. Non-cirrhotic patients received Ledipasvir/Sofosbuvir (LDV/SOF) 90/400mg for 12 weeks and cirrhotic patients received LDV/SOF with Ribavirin (RBV) for 12 weeks and without RBV for 24 weeks. The treatment efficacy in terms of sustained virological response (SVR12) was monitored 12 weeks post-treatment. The safety profile, and health-related quality of life (HRQoL) were monitored from baseline to follow-up visits. Results Two hundred and ninety out of 309 (93.85%) non-cirrhotic and 31 out of 33 (93.94%) compensated cirrhotic patients achieved SVR-12. The safety profile of the non-cirrhotic and compensated cirrhotic patients was comparable throughout the study duration. Fatigue was the most commonly reported adverse event (AE) in non-cirrhotic and compensated cirrhotic patients, followed by headache, nausea, and fever. The HRQoL improved from baseline to follow-up visits among patients of both groups. Conclusion It is concluded that LDV and SOF combination regimen is safe and effective for treating Genotype-3 HCV patients without cirrhosis/compensated cirrhosis, and also improves the patient's HRQoL.
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Affiliation(s)
- Zahid Yaseen Hashmi
- Dr. Zahid Yaseen Hashmi, FCPS Medicine. Chairman Liver Foundation Trust, Faisalabad, Pakistan
| | - Sandeed Hashmi
- Dr. Sandeed Hashmi, MBBS. Liver Centre Faisalabad, Pakistan
| | - Ali Raza
- Dr. Ali Raza, MBBS. Liver Centre Faisalabad, Pakistan
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9
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Szilveszter RM, Muntean M, Florea A. Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments-An Overview. Biomolecules 2024; 14:656. [PMID: 38927059 PMCID: PMC11201617 DOI: 10.3390/biom14060656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial-mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages-predominantly with a pro-tumoral role-hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines.
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Affiliation(s)
- Raluca-Margit Szilveszter
- Department of Pathology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400340 Cluj-Napoca, Romania
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
- Cluj County Emergency Clinical Hospital, 400340 Cluj-Napoca, Romania
| | - Mara Muntean
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
| | - Adrian Florea
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
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Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms 2024; 12:1035. [PMID: 38930417 PMCID: PMC11205832 DOI: 10.3390/microorganisms12061035] [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: 04/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Roaa Khalil
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
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11
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Benetti F, de Araújo A, de Maman Júnior I, Coelho Borges Cheinquer C, Herz Wolff F, Cheinquer H. Impact of sustained virologic response on glucose parameters among patients with chronic hepatitis C treated with direct-acting antivirals. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e220480. [PMID: 38709148 PMCID: PMC11081048 DOI: 10.20945/2359-4292-2022-0480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 08/09/2023] [Indexed: 05/07/2024]
Abstract
Objective The aim of this study was to evaluate the glycated hemoglobin (HbA1c) levels before and after sustained virologic response (SVR) and investigate the baseline characteristics associated with improved glycemic control in patients with chronic hepatitis C (CHC) achieving SVR after directacting antivirals (DAA) therapy. Materials and methods Consecutive adult patients with CHC who achieved SVR after DAA treatment between January 2016 and December 2017 at Hospital de Clínicas de Porto Alegre (RS, Brazil) were prospectively included. Levels of HbA1c were measured up to 24 weeks before DAA therapy and 12 weeks after SVR. Exclusion criteria were decompensated cirrhosis, HIV and/or hepatitis B virus, liver disease of other etiologies, and/or modification of prediabetes/ type 2 diabetes mellitus (PDM/T2DM) management. The primary outcome was a comparison of HbA1c levels before and after SVR. Secondary outcomes were the baseline variables associated with improved glycemic control. Results The study included 207 patients with a mean age of 60.6±10.7 years, of whom 51.7% were women, 56% had cirrhosis, 37.7% had HCV genotype 3, and 54.5% had baseline T2DM or PDM. The median HbA1c level reduced significantly after SVR (5.5%, interquartile range [IQR] 4.9%-6.3%) compared with baseline (5.7%, IQR 5.3%-6.7%; p = 0.01). The baseline characteristics associated with improved HbA1c after SVR were cirrhosis, genotype 3, and age ≤ 60 years. Conclusion Among patients with CHC, SVR after DAA was associated with HbA1c reduction, particularly in those with cirrhosis, genotype 3, and age ≤ 60 years.
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Affiliation(s)
- Fábia Benetti
- Programa de Pós-graduação em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Alexandre de Araújo
- Programa de Pós-graduação em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Divisão de Gastroenterologia e Hepatologia do Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Italo de Maman Júnior
- Programa de Pós-graduação em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | | | - Fernando Herz Wolff
- Programa de Pós-graduação em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Hugo Cheinquer
- Programa de Pós-graduação em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil,
- Divisão de Gastroenterologia e Hepatologia do Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil,
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12
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Farooq HZ, James M, Abbott J, Oyibo P, Divall P, Choudhry N, Foster GR. Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review. World J Gastrointest Oncol 2024; 16:1596-1612. [PMID: 38660636 PMCID: PMC11037048 DOI: 10.4251/wjgo.v16.i4.1596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/21/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.
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Affiliation(s)
- Hamzah Z Farooq
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Michael James
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Jane Abbott
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Patrick Oyibo
- School of Health and Psychological Sciences, University of London, London EC1V 0HB, United Kingdom
| | - Pip Divall
- University Hospitals of Leicester Library, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, United Kingdom
| | - Naheed Choudhry
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
| | - Graham R Foster
- Blizard Institute, Queen Mary University of London, London E1 2AT, United Kingdom
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Tsukanov VV, Savchenko AA, Cherepnin MA, Vasyutin AV, Kasparov EV, Belenyuk VD, Tonkikh JL, Borisov AG. Subpopulation composition of blood T-helpers in hepatitis C patients with genotype 1 or 3. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:168-176. [DOI: 10.21518/ms2023-447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Introduction. Despite advances in treatment, the problem of chronic viral hepatitis C (CVHC) remains very relevant for Russia. There is a debate about which of the most common genotypes in our country: 1 or 3, has a more aggressive course of CVHC. Patients with CVHC exhibit dysfunction of T-cell immunity, many aspects of which remain unclear.Aim. To research the subpopulation composition of blood T-helpers in patients with genotypes 1 and 3 of chronic viral hepatitis C (CVHC) depending on the severity of clinical and morphological manifestations.Materials and methods. Clinical, laboratory examination and determination of liver fibrosis by elastometry using the METAVIR scale were performed in 297 patients with CVHC genotype 1, 231 patients with CVHC genotype 3, and 20 healthy individuals in the control group. The study of the subpopulation composition of T-helpers in the blood by flow cytometry (Navios, Beckman Coulter, USA) with the determination of markers CD3, CD4, CD45R0 and CD62L was carried out in 74 patients with CVHC genotype 1, 70 patients with CVHC genotype 3 and 20 people in the control group.Results. Naive T-helpers (CD3+CD4+CD45RO-CD62L+), T-helpers of central (CD3+CD4+CD45R0+CD62L+) and effector memory (CD3+CD4+CD45R0+CD62L–) in the blood decreased with an increase in the severity of fibrosis and inflammation activity in the liver in both examined groups. In patients with CVHC genotype 3, the content of TEMRA T-helpers (CD3+CD4+CD45R0-CD62L-) in the blood under these conditions sharply decreased (Kruskal – Wallis test, respectively, p = 0.04 and p = 0.02). In patients with CVHC genotype 1, no such patterns were registered (Kruskal – Wallis test, respectively, p = 0.8 and p = 0.87).Conclusion. A direct correlation was determined between the deterioration of the indicators of the blood T-helpers subpopulation composition with an increase in the severity of fibrosis and inflammation activity in the liver in patients with chronic hepatitis C, which had some differences in patients with genotypes 1 and 3.
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Affiliation(s)
- V. V. Tsukanov
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - A. A. Savchenko
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - M. A. Cherepnin
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - A. V. Vasyutin
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - E. V. Kasparov
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - V. D. Belenyuk
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - Ju. L. Tonkikh
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
| | - A. G. Borisov
- Krasnoyarsk Science Centre of the Siberian Branch of Russian Academy of Science, Scientific Research Institute of Medical Problems of the North
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Reingardt DE, Ostankova YV, Lyalina LV, Anufrieva EV, Semenov AV, Totolian AA. Distribution of hepatitis С virus drug resistance mutations among patients with recurrence of the disease during therapy with direct antiviral drugs. HIV INFECTION AND IMMUNOSUPPRESSIVE DISORDERS 2024; 15:86-93. [DOI: 10.22328/2077-9828-2023-15-4-86-93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
The aim of the study was to identify the prevalence of drug resistance mutations in the hepatitis C virus among patients with relapse of the disease on therapy with direct antiviral drugs.Materials and methods. The study material included 31 blood plasma samples from patients with chronic hepatitis C with relapse of the disease on therapy with direct antiviral drugs. Samples were screened for the presence of HCV RNA. In case of detection of HCV RNA, amplification was carried out using a set of primers jointly flanking the NS3, NS5A, NS5B genes. After sequencing the nucleotide sequences of these genes, the subtype of the virus was determined and drug resistance mutations were identified.Results and discussion. The age of the patients ranged from 33 to 62 and averaged 45.8±8.38 years. The number of men in the group prevailed compared to women — 21 (67%) and 10 (33%), respectively. Viral load determination results ranged from 3.1×103 to 4.2×107 IU/ml. The distribution of genotypes was as follows: 1a — 26% (n=8), 1b — 29% (n=9), 3a — 45% (n=14). The nucleotide sequence of the NS3, NS5A, NS5B regions was determined in all samples. Mutations associated with drug resistance were detected in 87% (n=27). In all identified cases, the mutations resulted in viral resistance to at least one drug included in the patient’s current treatment regimen. In one patient, amino acid substitutions were found in three regions at once, which led to the emergence of resistance to two drugs in the regimen.Conclusion. Conducting a preliminary examination of patients to identify mutations of drug resistance to direct antiviral drugs can affect the effectiveness of the planned treatment and the choice of the optimal regimen.
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Affiliation(s)
| | | | | | | | - A. V. Semenov
- State Scientific Center of Virology and Biotechnology «Vector»
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15
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Lim AG, Aas CF, Çağlar ES, Vold JH, Fadnes LT, Vickerman P, Johansson KA. Cost-effectiveness of integrated treatment for hepatitis C virus (HCV) among people who inject drugs in Norway: An economic evaluation of the INTRO-HCV trial. Addiction 2023; 118:2424-2439. [PMID: 37515462 PMCID: PMC10952903 DOI: 10.1111/add.16305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 06/26/2023] [Indexed: 07/30/2023]
Abstract
BACKGROUND AND AIMS The INTRO-HCV randomized controlled trial conducted in Norway over 2017-2019 found that integrated treatment, compared with standard-of-care hospital treatment, for hepatitis C virus (HCV) with direct-acting antivirals (DAAs) improved treatment outcomes among people who inject drugs (PWID). We evaluated cost-effectiveness of the INTRO-HCV intervention. DESIGN A Markov health state transition model of HCV disease progression and treatment with cost-effectiveness analysis from the health-provider perspective. Primary cost, utility, and health outcome data were derived from the trial. Costs and health benefits (quality-adjusted life-years, QALYs) were tracked over 50 years. Probabilistic and univariate sensitivity analyses investigated DAA price reductions and variations in HCV treatment and disease care cost assumptions, using costs from different countries (Norway, United Kingdom, United States, France, Australia). SETTING AND PARTICIPANTS PWID attending community-based drug treatment centers for people with opioid dependence in Norway. MEASUREMENTS Incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained, compared against a conventional (€70 000/QALY) willingness-to-pay threshold for Norway and lower (€20 000/QALY) threshold common among high-income countries. FINDINGS Integrated treatment resulted in an ICER of €13 300/QALY gained, with 99% and 71% probability of being cost-effective against conventional and lower willingness-to-pay thresholds, respectively. A 30% lower DAA price reduced the ICER to €6 900/QALY gained, with 91% probability of being cost-effective at the lower willingness-to-pay threshold. A 60% and 90% lower DAA price had 36% and >99% probability of being cost-saving, respectively. Sensitivity analyses suggest integrated treatment was cost-effective at the lower willingness-to-pay threshold (>60% probability) across different assumptions on HCV treatment and disease care costs with 30% DAA price reduction, and became cost-saving with 60%-90% price reductions. CONCLUSIONS Integrated hepatitis C virus treatment for people who inject drugs in community settings is likely cost-effective compared with standard-of-care referral pathways in Norway and may be cost-saving in settings with particular characteristics.
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Affiliation(s)
- Aaron Guanliang Lim
- Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
| | - Christer Frode Aas
- Bergen Addiction Research, Department of Addiction MedicineHaukeland University HospitalBergenNorway
- Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
- Division of PsychiatryHaukeland University HospitalBergenNorway
| | - Ege Su Çağlar
- Bergen Addiction Research, Department of Addiction MedicineHaukeland University HospitalBergenNorway
- Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
| | - Jørn Henrik Vold
- Bergen Addiction Research, Department of Addiction MedicineHaukeland University HospitalBergenNorway
- Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
- Division of PsychiatryHaukeland University HospitalBergenNorway
| | - Lars Thore Fadnes
- Bergen Addiction Research, Department of Addiction MedicineHaukeland University HospitalBergenNorway
- Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
| | - Peter Vickerman
- Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
| | - Kjell Arne Johansson
- Bergen Addiction Research, Department of Addiction MedicineHaukeland University HospitalBergenNorway
- Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
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16
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Kanwal F, Khaderi S, Singal AG, Marrero JA, Asrani SK, Amos CI, Thrift AP, Kramer JR, Yu X, Cao Y, Luster M, Al-Sarraj A, Ning J, El-Serag HB. Risk Stratification Model for Hepatocellular Cancer in Patients With Cirrhosis. Clin Gastroenterol Hepatol 2023; 21:3296-3304.e3. [PMID: 37390101 PMCID: PMC10661677 DOI: 10.1016/j.cgh.2023.04.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 04/07/2023] [Accepted: 04/13/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND & AIMS The available risk stratification indices for hepatocellular cancer (HCC) have limited applicability. We developed and externally validated an HCC risk stratification index in U.S. cohorts of patients with cirrhosis. METHODS We used data from 2 prospective U.S. cohorts to develop the risk index. Patients with cirrhosis were enrolled from 8 centers and followed until development of HCC, death, or December 31, 2021. We identified an optimal set of predictors with the highest discriminatory ability (C-index) for HCC. The predictors were refit using competing risk regression and its predictive performance was evaluated using the area under the receiver-operating characteristic curve (AUROC). External validation was performed in a cohort of 21,550 patients with cirrhosis seen in the U.S Veterans Affairs system between 2018 and 2019 with follow-up through 2021. RESULTS We developed the model in 2431 patients (mean age 60 years, 31% women, 24% cured hepatitis C, 16% alcoholic liver disease, and 29% nonalcoholic fatty liver disease). The selected model had a C-index of 0.77 (95% confidence interval [CI], 0.73-0.81), and the predictors were age, sex, smoking, alcohol use, body mass index, etiology, α-fetoprotein, albumin, alanine aminotransferase, and platelet levels. The AUROCs were 0.75 (95% CI, 0.65-0.85) at 1 year and 0.77 (95% CI, 0.71-0.83) at 2 years, and the model was well calibrated. In the external validation cohort, the AUROC at 2 years was 0.70 with excellent calibration. CONCLUSION The risk index, including objective and routinely available risk factors, can differentiate patients with cirrhosis who will develop HCC and help guide discussions regarding HCC surveillance and prevention. Future studies are needed for additional external validation and refinement of risk stratification.
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Affiliation(s)
- Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas; VA HSR&D Center for Innovatio ns in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
| | - Saira Khaderi
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Amit G Singal
- Division of Digestive and Liver Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Jorge A Marrero
- Division of Digestive and Liver Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Sumeet K Asrani
- Division of Gastroenterology, Department of Medicine, Baylor University Medical Center, Dallas, Texas
| | - Christopher I Amos
- Section of Epidemiology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Aaron P Thrift
- Section of Epidemiology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jennifer R Kramer
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas; VA HSR&D Center for Innovatio ns in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Xian Yu
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas; VA HSR&D Center for Innovatio ns in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Yumei Cao
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas; VA HSR&D Center for Innovatio ns in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Michelle Luster
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Abeer Al-Sarraj
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas; VA HSR&D Center for Innovatio ns in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Jing Ning
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas; VA HSR&D Center for Innovatio ns in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
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17
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Martinello M, Solomon SS, Terrault NA, Dore GJ. Hepatitis C. Lancet 2023; 402:1085-1096. [PMID: 37741678 DOI: 10.1016/s0140-6736(23)01320-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 05/30/2023] [Accepted: 06/22/2023] [Indexed: 09/25/2023]
Abstract
Hepatitis C virus (HCV) is a hepatotropic RNA virus that can cause acute and chronic hepatitis, with progressive liver damage resulting in cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In 2016, WHO called for the elimination of HCV infection as a public health threat by 2030. Despite some progress, an estimated 57 million people were living with HCV infection in 2020, and 300 000 HCV-related deaths occur per year. The development of direct-acting antiviral therapy has revolutionised clinical care and generated impetus for elimination, but simplified and broadened HCV screening, enhanced linkage to care, and higher coverage of treatment and primary prevention strategies are urgently required.
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Affiliation(s)
- Marianne Martinello
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; Department of Infectious Diseases, Prince of Wales Hospital, Sydney, NSW, Australia.
| | - Sunil S Solomon
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Norah A Terrault
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA, USA
| | - Gregory J Dore
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; Department of Infectious Diseases, St Vincent's Hospital, Sydney, NSW, Australia
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18
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Choi JH, Thung SN. Advances in Histological and Molecular Classification of Hepatocellular Carcinoma. Biomedicines 2023; 11:2582. [PMID: 37761023 PMCID: PMC10526317 DOI: 10.3390/biomedicines11092582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by hepatocellular differentiation. HCC is molecularly heterogeneous with a wide spectrum of histopathology. The prognosis of patients with HCC is generally poor, especially in those with advanced stages. HCC remains a diagnostic challenge for pathologists because of its morphological and phenotypic diversity. However, recent advances have enhanced our understanding of the molecular genetics and histological subtypes of HCC. Accurate diagnosis of HCC is important for patient management and prognosis. This review provides an update on HCC pathology, focusing on molecular genetics, histological subtypes, and diagnostic approaches.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu 42415, Republic of Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA;
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19
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Lu M, Salgia R, Li J, Trudeau S, Rupp LB, Wu T, Daida YG, Schmidt MA, Gordon SC. Dynamic risk assessment for hepatocellular carcinoma in patients with chronic hepatitis C. J Viral Hepat 2023; 30:746-755. [PMID: 37415492 DOI: 10.1111/jvh.13859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 05/27/2023] [Indexed: 07/08/2023]
Abstract
Chronic hepatitis C (HCV) is a primary cause of hepatocellular carcinoma (HCC). Although antiviral treatment reduces risk of HCC, few studies quantify the impact of treatment on long-term risk in the era of direct-acting antivirals (DAA). Using data from the Chronic Hepatitis Cohort Study, we evaluated the impact of treatment type (DAA, interferon-based [IFN], or none) and outcome (sustained virological response [SVR] or treatment failure [TF]) on risk of HCC. We then developed and validated a predictive risk model. 17186 HCV patients were followed until HCC, death or last follow-up. We used extended landmark modelling, with time-varying covariates and propensity score justification and generalized estimating equations with a link function for discrete time-to-event data. Death was considered a competing risk. We observed 586 HCC cases across 104,000 interval-years of follow-up. SVR from DAA or IFN-based treatment reduced risk of HCC (aHR 0.13, 95% CI 0.08-0.20; and aHR 0.45, 95% CI 0.31-0.65); DAA SVR reduced risk more than IFN SVR (aHR 0.29, 95% CI 0.17-0.48). Independent of treatment, cirrhosis was the strongest risk factor for HCC (aHR 3.94, 95% CI 3.17-4.89 vs. no cirrhosis). Other risk factors included male sex, White race and genotype 3. Our six-variable predictive model had 'excellent' accuracy (AUROC 0.94) in independent validation. Our novel landmark interval-based model identified HCC risk factors across antiviral treatment status and interactions with cirrhosis. This model demonstrated excellent predictive accuracy in a large, racially diverse cohort of patients and could be adapted for 'real world' HCC monitoring.
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Affiliation(s)
- Mei Lu
- Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA
| | - Reena Salgia
- Department of Gastroenterology and Hepatology, Henry Ford Health, Detroit, Michigan, USA
- School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Jia Li
- Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA
- School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Sheri Trudeau
- Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA
| | - Loralee B Rupp
- Department of Health Policy and Health Services Research, Henry Ford Health, Detroit, Michigan, USA
| | - Trueman Wu
- Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA
| | - Yihe G Daida
- Center for Integrated Health Care Research, Kaiser Permanente Hawaii, Honolulu, Hawaii, USA
| | - Mark A Schmidt
- Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA
| | - Stuart C Gordon
- Department of Gastroenterology and Hepatology, Henry Ford Health, Detroit, Michigan, USA
- School of Medicine, Wayne State University, Detroit, Michigan, USA
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20
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Jančorienė L, Rozentāle B, Tolmane I, Jēruma A, Salupere R, Buivydienė A, Valantinas J, Kupčinskas L, Šumskienė J, Čiupkevičienė E, Ambrozaitis A, Golubovska O, Moroz L, Flisiak R, Bondar B. Genotype Distribution and Characteristics of Chronic Hepatitis C Infection in Estonia, Latvia, Lithuania, and Ukraine: The RESPOND-C Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1577. [PMID: 37763696 PMCID: PMC10534763 DOI: 10.3390/medicina59091577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023]
Abstract
Background and objectives: Since 2013, highly effective direct-acting antiviral (DAA) treatment for chronic hepatitis C (CHC) has become available, with cure rates exceeding 95%. For the choice of optimal CHC treatment, an assessment of the hepatitis C virus (HCV) genotype (GT) and liver fibrosis stage is necessary. Information about the distribution of these parameters among CHC patients in Estonia, Latvia, and Lithuania (the Baltic states) and especially in Ukraine is scarce. This study was performed to obtain epidemiologic data regarding CHC GT and fibrosis stage distribution for better planning of resources and prioritization of patients for DAA drug treatment according to disease severity in high-income (the Baltic states) and lower-middle-income (Ukraine) countries. Materials and methods: The retrospective RESPOND-C study included 1451 CHC patients. Demographic and disease information was collected from medical charts for each patient. Results: The most common suspected mode of viral transmission was blood transfusions (17.8%), followed by intravenous substance use (15.7%); however, in 50.9% of patients, the exact mode of transmission was not clarified. In Ukraine (18.4%) and Estonia (26%), transmission by intravenous substance use was higher than in Lithuania (5%) and Latvia (5.3%). Distribution of HCV GT among patients with CHC was as follows: GT1-66.4%; GT3-28.1; and GT2-4.1%. The prevalence of GT1 was the highest in Latvia (84%) and the lowest in Ukraine (63%, p < 0.001). Liver fibrosis stages were distributed as follows: F0-12.2%, F1-26.3%, F2-23.5%, F3-17.1%, and F4-20.9%. Cirrhosis (F4) was more prevalent in Lithuanian patients (30.1%) than in Estonians (8.1%, p < 0.001). Conclusions: This study contributes to the knowledge of epidemiologic characteristics of HCV infection in the Baltic states and Ukraine. The data regarding the patterns of HCV GT and fibrosis stage distribution will be helpful for the development of national strategies to control HCV infection in the era of DAA therapy.
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Affiliation(s)
- Ligita Jančorienė
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Medical Faculty, Vilnius University, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania
| | - Baiba Rozentāle
- Latvian Centre of Infectious Diseases, Riga East Clinical University Hospital, LV-1006 Riga, Latvia
| | - Ieva Tolmane
- Latvian Centre of Infectious Diseases, Riga East Clinical University Hospital, LV-1006 Riga, Latvia
- Faculty of Medicine, University of Latvia, LV-1586 Riga, Latvia
| | - Agita Jēruma
- Latvian Centre of Infectious Diseases, Riga East Clinical University Hospital, LV-1006 Riga, Latvia
- Faculty of Medicine, Riga Stradins University, LV-1007 Riga, Latvia
| | - Riina Salupere
- Tartu University Hospital, University of Tartu, EE-50406 Tartu, Estonia
| | - Arida Buivydienė
- Clinic of Gastroenterology, Nephrourology and Surgery, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania
- Centre of Hepatology, Gastroenterology and Dietetics, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania
| | - Jonas Valantinas
- Clinic of Gastroenterology, Nephrourology and Surgery, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania
- Centre of Hepatology, Gastroenterology and Dietetics, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania
| | - Limas Kupčinskas
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Jolanta Šumskienė
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Eglė Čiupkevičienė
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
- Health Research Institute, Faculty of Public Health, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania
| | - Arvydas Ambrozaitis
- Clinic of Infectious Diseases and Dermatovenerology, Institute of Clinical Medicine, Medical Faculty, Vilnius University, Vilnius University Hospital Santaros Klinikos, LT-08406 Vilnius, Lithuania
| | - Olga Golubovska
- Infectious Disease Department, O.O. Bogomolets National Medical University, 01601 Kyiv, Ukraine
| | - Larysa Moroz
- Department of Infectious Diseases with the Course of Epidemiology, National Pirogov Memorial Medical University, 21018 Vinnytsya, Ukraine
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Borys Bondar
- AbbVie Biopharmaceuticals GmbH, 01032 Kyiv, Ukraine
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21
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Tang Q, Chen Z, Li H, Zhang L, Peng M, Zeng Y, Liu X, Liu Z, Hu P. Molecular epidemiology of hepatitis C virus genotypes in different geographical regions of Chinese mainland and a phylogenetic analysis. Infect Dis Poverty 2023; 12:66. [PMID: 37430328 DOI: 10.1186/s40249-023-01106-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/16/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection remains a major public health problem in Chinese mainland. Investigation of the distribution of genotypes contributed to the prevention, diagnosis and treatment of HCV infection. Therefore, we conducted a study on the distribution of HCV genotypes and phylogenetic analysis to provide an up-to-date understanding of the molecular epidemiology of genotypes in Chinese mainland. METHODS Our retrospective multicenter study enrolled 11,008 samples collected between August 2018 and July 2019 from 29 provinces/municipalities (Beijing, Hebei, Inner Mongolia, Shanxi, Tianjin, Gansu, Ningxia, Shaanxi, Xinjiang, Heilongjiang, Jilin Liaoning, Henan, Hubei Hunan, Anhui, Fujian, Jiangsu, Jiangxi, Shandong, Shanghai Zhejiang, Guangdong, Guangxi, Hainan, Chongqing, Guizhou, Sichuan and Yunnan). Phylogenetic analysis of each subtype was performed to infer the evolutionary relationship of sequences from diverse regions. Two independent samples t tests were used for the comparison of continuous variables, and chi-square tests were used for the comparison of categorical variables. RESULTS Four genotypes (1, 2, 3 and 6) were found, including 14 subtypes. HCV genotype 1 was dominant, accounting for 49.2%, followed by genotypes 2, 3 and 6, accounting for 22.4%, 16.4%, and 11.9%, respectively. Additionally, the top five subtypes were 1b, 2a, 3b, 6a and 3a. Proportions of genotypes 1 and 2 decreased while genotypes 3 and 6 increased over past years (P < 0.001). Genotypes 3 and 6 were concentrated in the population aged 30 to 50 years, and male carriers had lower proportions of subtypes 1b and 2a than female carriers (P < 0.01). Genotypes 3 and 6 were more prevalent in southern parts of Chinese mainland. Nationwide spreads of subtypes 1b and 2a were associated with sequences from northern parts of Chinese mainland, while subtypes 3a, 3b and 6a were associated with sequences from southern parts of Chinese mainland. CONCLUSIONS HCV subtypes 1b and 2a remained the most common subtypes in Chinese mainland, and their proportions decreased over the past years, while the proportions of genotypes 3 and 6 increased. Our investigation provided an accurate epidemiological picture of the circulating viral strains in Chinese mainland, contributing to the prevention, diagnosis and treatment of HCV infection. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Qiao Tang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Zhiwei Chen
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Hu Li
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Li Zhang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Mingli Peng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Yi Zeng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Xiaoqing Liu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China
| | - Zubi Liu
- Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, Hangzhou, Zhejiang, China.
- Zhejiang University School of Medicine, Hangzhou, 310000, China.
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Chinese Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Yuzhong District, Chongqing, 400000, China.
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22
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Fakoury MK, Schmidt SL, Brandão Mello CE, Filho ADC, Amendola Pires MM. Cognitive Performance in Asymptomatic Elderly People with Hepatitis C: The Role of Education. J Clin Med 2023; 12:4588. [PMID: 37510703 PMCID: PMC10380825 DOI: 10.3390/jcm12144588] [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: 06/02/2023] [Revised: 07/05/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Neurotropism of the hepatitis C virus (HCV) can be the source of subtle neuropsychological symptoms in non-cirrhotic patients. Age is a risk factor for cognitive impairment (CI). Thus, asymptomatic elderly people who carry HCV might be at a greater risk of CI. Education can influence test performance. OBJECTIVES (1) To verify whether elderly people with HCV performed poorer than controls on cognitive tests. (2) To analyze how education affects performance. (3) To verify whether the extent of the effect of education on performance depends on the group (HCV vs. controls) and the type of cognitive test. METHODS Asymptomatic HCV carriers older than 60 years (n = 41) were matched with 41 corresponding controls. All participants performed the following tests: Mini-Cog, Mini Mental State Examination, clock drawing test (CDT), and verbal fluency. RESULTS (1) There were no significant differences in cognitive performance between the two groups. (2) Higher education was always associated with better performance. (3) There was a significant group difference in the slopes of the regression lines between years of education and CDT performance. No differences were found for the other three tests. CONCLUSION Considering the scores on the CDT, the rate of improvement in performance when schooling increases is higher in HCV carriers.
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Affiliation(s)
- Max Kopti Fakoury
- Department of Internal Medicine, Gaffrée and Guinle University Hospital, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- Graduate Program in Neurology, Department of Neurology, PPGNEURO-UNIRIO, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- Laboratory of Behavioral Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- RENASCER Multidisciplinary Program of the Third Age, Gaffrée and Guinle University Hospital, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
| | - Sergio Luis Schmidt
- Graduate Program in Neurology, Department of Neurology, PPGNEURO-UNIRIO, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- Laboratory of Behavioral Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- RENASCER Multidisciplinary Program of the Third Age, Gaffrée and Guinle University Hospital, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
| | - Carlos Eduardo Brandão Mello
- Department of Internal Medicine, Gaffrée and Guinle University Hospital, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- Graduate Program in Neurology, Department of Neurology, PPGNEURO-UNIRIO, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- Graduate Program in HIV/AIDS Infection and Viral Hepatitis, PPGHIV/HV-UNIRIO, School of Medicine and Surgery, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
| | - Aureo do Carmo Filho
- Graduate Program in Neurology, Department of Neurology, PPGNEURO-UNIRIO, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
- Laboratory of Behavioral Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
| | - Marcia Maria Amendola Pires
- Graduate Program in Neurology, Department of Neurology, PPGNEURO-UNIRIO, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-853, Brazil
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23
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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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24
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Gull N, Arshad F, Naikoo GA, Hassan IU, Pedram MZ, Ahmad A, Aljabali AAA, Mishra V, Satija S, Charbe N, Negi P, Goyal R, Serrano-Aroca Á, Al Zoubi MS, El-Tanani M, Tambuwala MM. Recent Advances in Anticancer Activity of Novel Plant Extracts and Compounds from Curcuma longa in Hepatocellular Carcinoma. J Gastrointest Cancer 2023; 54:368-390. [PMID: 35285010 PMCID: PMC8918363 DOI: 10.1007/s12029-022-00809-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE Among all forms of cancers, hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. There are several treatment options for HCC ranging from loco-regional therapy to surgical treatment. Yet, there is high morbidity and mortality. Recent research focus has shifted towards more effective and less toxic cancer treatment options. Curcumin, the active ingredient in the Curcuma longa plant, has gained widespread attention in recent years because of its multifunctional properties as an antioxidant, anti-inflammatory, antimicrobial, and anticancer agent. METHODS A systematic search of PubMed, Embase and Google Scholar was performed for studies reporting incidence of HCC, risk factors associated with cirrhosis and experimental use of curcumin as an anti-cancer agent. RESULTS This review exclusively encompasses the anti-cancer properties of curcumin in HCC globally and it's postulated molecular targets of curcumin when used against liver cancers. CONCLUSIONS This review is concluded by presenting the current challenges and future perspectives of novel plant extracts derived from C. longa and the treatment options against cancers.
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Affiliation(s)
- Nighat Gull
- School of Sciences, Maulana Azad National Urdu University, 32, Hyderabad, TS, India
| | - Fareeha Arshad
- Department of Biochemistry, Aligarh Muslim University, U.P., India
| | - Gowhar A Naikoo
- Department of Mathematics and Sciences, College of Arts and Applied Sciences, Dhofar University, Salalah, Sultanate of Oman.
| | - Israr Ul Hassan
- College of Engineering, Dhofar University, Salalah, Sultanate of Oman
| | - Mona Zamani Pedram
- Faculty of Mechanical Engineering-Energy Division, K. N. Toosi University of Technology, P.O. Box: 19395-1999, No. 15-19, Pardis St., Mollasadra Ave., Vanak Sq., Tehran, 1999 143344, Iran
| | - Arif Ahmad
- School of Sciences, Maulana Azad National Urdu University, 32, Hyderabad, TS, India
| | - Alaa A A Aljabali
- Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid, 21163, Jordan
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Nitin Charbe
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, 78363, USA
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan, 173229, India
| | - Rohit Goyal
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan, 173229, India
| | - Ángel Serrano-Aroca
- Biomaterials & Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia, San Vicente Mártir, 46001, Valencia, Spain
| | - Mazhar S Al Zoubi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Mohamed El-Tanani
- Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Murtaza M Tambuwala
- School of Pharmacy & Pharmaceutical Sciences, Ulster University, Northern Ireland, Coleraine, BT52 1SA, County Londonderry, UK.
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25
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Cherepnin MA, Tsukanov VV, Savchenko AA, Vasyutin AV, Borisov AG, Belenyuk VD, Tonkikh JL. Subpopulation composition of blood T-killers in patients with hepatitis C with genotype 1 or 3. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2023:142-149. [DOI: 10.21518/ms2023-139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Introduction. Despite great attention to the pathogenesis of chronic viral hepatitis C (CVHC), many aspects of the immune response in this pathology remain unclear. Aim. To study the subpopulation composition of blood cytotoxic T cells by flow cytometry, depending on the severity of clinical and morphological manifestations of CVHC with genotype 1 or 3. Materials and methods. Clinical, laboratory examinations, determination of liver fibrosis by elastometry using the METAVIR scale and study of the subpopulation composition of cytotoxic T cells in the blood were carried out in 144 patients with CVHC, including 74 patients with genotype 1 and 70 individuals with genotype 3, and in 20 people of the control group. The study of the subpopulation composition of cytotoxic T cells in the blood was carried out on a flow cytometer Navios (Beckman Coulter, USA) with the determination of CD3, CD8, CD45R0 and CD62L markers. Results. Changes in the subpopulation composition of blood cytotoxic T cells were more associated with the severity of liver fibrosis in patients with 1 and 3 genotypes of CVHC, than with inflammatory activity and viral load. In patients with CVHC genotype 3, a marked decrease in the content of TEMRA T-cytotoxic cells (CD3+ CD8+ CD45R0–CD62L–) and effector memory T-cytotoxic cells (CD3+ CD8+ CD45R0+ CD62L–) was registered in patients with METAVIR liver fibrosis stage F3-F4 in comparison with persons with METAVIR liver fibrosis stage F0-F1 (Kruskal-Wallis test, respectively, p = 0.02 and p = 0.04 In persons with CVHC genotype 1, similar associations were expressed to a lesser extent.Conclusion. We obtained an association of deterioration in the indices of the blood cytotoxic T cells subpopulation in patients with CVHC with an increase in the severity of liver fibrosis, which had some differences in patients with genotypes 1 and 3.
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Affiliation(s)
- M. A. Cherepnin
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - V. V. Tsukanov
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - A. A. Savchenko
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - A. V. Vasyutin
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - A. G. Borisov
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - V. D. Belenyuk
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
| | - J. L. Tonkikh
- Krasnoyarsk Science Center” of the Siberian Branch of the Russian Academy of Sciences”, Separate Subdivision “Scientific Research Institute of medical problems of the North”
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26
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Medhioub M, Khsiba A, Mahmoudi M, Ben Mohamed A, Yakoubi M, Hamzaoui L. Performance de l’ADRESS-HCC score dans l‘évaluation du risque
de carcinome hépatocellulaire. LA TUNISIE MEDICALE 2023; 101:420-425. [PMID: 38372534 PMCID: PMC11217958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 07/11/2023] [Indexed: 07/05/2024]
Abstract
INTRODUCTION The ADRESS-HCC score allows predicting the risk of occurrence of Hepatocellular carcinoma in cirrhosis at one year of follow-up. AIM Measuring the performance of ADRESS-HCC in predicting the risk of degeneration on post-viral cirrhosis, in a gastroenterology department in Tunisia. METHODS Retrospective study, including patients followed for compensated viral cirrhosis in the gastroenterology department of the Mohamed Taher Maamouri hospital. The ADRESS-HCC score was calculated at diagnosis of cirrhosis. We divided patients into two groups depending on whether they developed Hepatocellular carcinoma or not. We evaluated the performance of the ADRESS-HCC score in predicting the risk of Hepatocellular carcinoma according to a threshold value. RESULTS We enrolled 60 patients; the mean age was 62 years. Twenty-five patients developed hepatocellular carcinoma during follow-up. The mean value of ADRESS-HCC score was 5.08. To predict the occurrence of hepatocellular carcinoma at 1 year of follow-up, the area under the curve of the ADRESS-HCC score was 0.74 (p=0.01). For a threshold value of 5.63 its sensitivity was 91 % with a negative predictive value of 95.83%. CONCLUSION The ADRESS-HCC score had an average performance in predicting degeneration in post-viral cirrhosis.
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Affiliation(s)
- Mouna Medhioub
- Department of Gastroenterology - Mohamed Taher Maamouri- Hospital, Nabeul- University of Tunis El Manar, Faculty of Medicine, Tunis
| | - Amal Khsiba
- Department of Gastroenterology - Mohamed Taher Maamouri- Hospital, Nabeul- University of Tunis El Manar, Faculty of Medicine, Tunis
| | - Moufida Mahmoudi
- Department of Gastroenterology - Mohamed Taher Maamouri- Hospital, Nabeul- University of Tunis El Manar, Faculty of Medicine, Tunis
| | - Asma Ben Mohamed
- Department of Gastroenterology - Mohamed Taher Maamouri- Hospital, Nabeul- University of Tunis El Manar, Faculty of Medicine, Tunis
| | - Manel Yakoubi
- Department of Gastroenterology - Mohamed Taher Maamouri- Hospital, Nabeul- University of Tunis El Manar, Faculty of Medicine, Tunis
| | - Lamine Hamzaoui
- Department of Gastroenterology - Mohamed Taher Maamouri- Hospital, Nabeul- University of Tunis El Manar, Faculty of Medicine, Tunis
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27
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Role of Genetic and Epigenetic Modifications in the Progression of Hepatocellular Carcinoma in Chronic HCV Patients. LIVERS 2023. [DOI: 10.3390/livers3010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a significant cause of mortality and morbidity among chronically infected HCV patients. It is established that HCV is a primary risk factor for HCC progression. The treatment of HCV infection has been transformed by the introduction of DAAs with high rates of virological clearance. The reduction in cirrhosis-related consequences, particularly HCC, is the long-term objective of DAAs therapy for HCV. Although the risk of developing HCC is decreased in HCV patients who achieve a disease-sustaining virological response, these patients are nevertheless at risk, especially those with severe fibrosis and cirrhosis. Previous studies have shown that HCV induce several mechanisms of hepatocarcinogenesis in the host’s hepatic micro- and macro-environment, which leads to HCC progression. In an HCV-altered environment, compensatory liver regeneration favors chromosomal instability and irreversible alterations, which encourage hepatocyte neoplastic transformation and the development of malignant clones. These mechanisms involve a series of genetic and epigenetic modifications including host genetic factors, dysregulation of several signaling pathways, histone, and DNA modifications including methylation and acetylation. This review highlights the genetic and epigenetic factors that lead to the development of HCC in chronic HCV-infected individuals and can be targeted for earlier HCC diagnosis and prevention.
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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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29
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Lei J, Yang S, Chen B, Zhang L, Yan T, Yang G, Chen Y, Li Y, Lu Y, Zuo S. Efficacy and Safety of Tyrosine Kinase Inhibitors Alone or Combination with Programmed Death-1 Inhibitors in Treating of Hepatitis C-Related Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:357-367. [PMID: 36891505 PMCID: PMC9987323 DOI: 10.2147/jhc.s392347] [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: 10/12/2022] [Accepted: 02/16/2023] [Indexed: 03/06/2023] Open
Abstract
Background Tyrosine kinase inhibitors (TKI) combined with programmed cell death-1 (PD-1) inhibitor is a potential treatment modality for patients with HCV-related unresectable hepatocellular carcinoma (uHCC). Methods The participants of the present work included the patients having HCV-related uHCC who were treated with TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center between June 2018 and June 2021. In addition, the patients were classified into RNA-positive and RNA-negative groups based on whether or not the baseline HCV RNA was detectable. The overall survival (OS) was used as the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were used as secondary endpoints. The adverse events were recorded and evaluated. Results Among the 67 patients contained this work, 43 patients were classified into the TKI group, while 24 patients formed the combination group. In relative to the TKI group, the combination group presented notably better median OS (21 months vs 13 months, p = 0.043) and median PFS (8 months vs 5 months, p = 0.005). No evident differences were observed between the two groups in terms of the DCR (58.1% vs 79.2%, p = 0.080), ORR (13.9% vs 25.0%, p = 0.425) and the incidence of grade 3-4 adverse events (34.8% vs 33.3%, p = 1.000). In addition, there existed no obvious difference between the RNA-positive group and RNA-negative group in terms of median OS (14 months vs 19 months, p = 0.578) and median PFS (4 months vs 6 months, p = 0.238). Conclusion The patients having HCV-related uHCC after being treated with the TKI and PD-1 inhibitor combination therapy exhibited a better prognosis and manageable toxicity compared to the patients who underwent TKI monotherapy.
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Affiliation(s)
- Jin Lei
- School of Clinical Medicine, Guizhou Medical University, Guiyang, People's Republic of China
| | - Sibo Yang
- School of Clinical Medicine, Guizhou Medical University, Guiyang, People's Republic of China
| | - Bowen Chen
- 302 Clinical Medical School, Peking University, Beijing, People's Republic of China
| | - Linzhi Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of the PLA General Hospital, Beijing, People's Republic of China
| | - Tao Yan
- Comprehensive Liver Cancer Center, the 5th Medical Center of the PLA General Hospital, Beijing, People's Republic of China
| | - Gangqi Yang
- School of Clinical Medicine, Guizhou Medical University, Guiyang, People's Republic of China
| | - Yue Chen
- School of Clinical Medicine, Guizhou Medical University, Guiyang, People's Republic of China
| | - Yinyin Li
- Comprehensive Liver Cancer Center, the 5th Medical Center of the PLA General Hospital, Beijing, People's Republic of China
| | - Yinying Lu
- School of Clinical Medicine, Guizhou Medical University, Guiyang, People's Republic of China.,Comprehensive Liver Cancer Center, the 5th Medical Center of the PLA General Hospital, Beijing, People's Republic of China.,Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua, Beijing, People's Republic of China
| | - Shi Zuo
- School of Clinical Medicine, Guizhou Medical University, Guiyang, People's Republic of China.,Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China
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30
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Tripathi SK, Pal A, Ghosh S, Goel A, Aggarwal R, Banerjee S, Das S. LncRNA NEAT1 regulates HCV-induced Hepatocellular carcinoma by modulating the miR-9-BGH3 axis. J Gen Virol 2022; 103. [PMID: 36748628 DOI: 10.1099/jgv.0.001809] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9-5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9-5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9-5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.
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Affiliation(s)
| | - Apala Pal
- Indian Institute of Science, Bangalore, India
| | - Suchandrima Ghosh
- Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Amit Goel
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rakesh Aggarwal
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Soma Banerjee
- Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Saumitra Das
- Indian Institute of Science, Bangalore, India.,National Institute of Biomedical Genomics, Kalyani, India
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31
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Rodrigues JPV, Campos GRF, Bittar C, Martinelli ADLC, Campos MSDA, Pereira LRL, Rahal P, Souza FF. Selection dynamics of HCV genotype 3 resistance-associated substitutions under direct-acting antiviral therapy pressure. Braz J Infect Dis 2022; 26:102717. [PMID: 36410397 PMCID: PMC9706524 DOI: 10.1016/j.bjid.2022.102717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/07/2022] [Accepted: 10/30/2022] [Indexed: 11/21/2022] Open
Abstract
The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF + DCV ± ribavirin (RBV) or SOF + peginterferon (PEG) + RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF + DCV ± RBV group and 80.0% for the SOF + PEG + RBV arm. Cirrhosis, prior treatment with interferon/PEG + RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.
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Affiliation(s)
- João Paulo Vilela Rodrigues
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
| | | | - Cintia Bittar
- Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista, São José do Rio Preto, SP, Brasil
| | | | - Marília Silveira de Almeida Campos
- Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Leonardo Régis Leira Pereira
- Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Paula Rahal
- Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista, São José do Rio Preto, SP, Brasil
| | - Fernanda Fernandes Souza
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Balbi E, Moreira JPDL, Luiz RR, Perez RDM, de Souza HSP. Time trends and geographic distribution of hepatocellular carcinoma in Brazil: An ecological study. Medicine (Baltimore) 2022; 101:e30614. [PMID: 36197232 PMCID: PMC9509041 DOI: 10.1097/md.0000000000030614] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing globally, and HCC is the fourth leading cause of cancer-related death. This ecological study aimed to investigate the time trends and geographic distribution of HCC in Brazil. Data from the Brazilian Health Public System were retrospectively collected from January 2005 to December 2018. Hospitalization and intrahospital lethality rates for HCC were stratified by age and sex. Hospitalization rates and associated lethality per 100,000 inhabitants in each municipality were included in a worksheet to build maps displaying the estimates and the geographic distribution of HCC. From 2005 to 2018, a total of 75,466 admissions for HCC were registered and the mean hospitalizations increased from 2.1 to 5.8/100,000 inhabitants (176%). The greatest increase occurred among patients older than 50, particularly in males above 70 years old. Prevalence rates increased throughout the country, with the highest levels detected in the South and Southeast. However, the increase was proportionally higher in the Northeast (377%), especially in municipalities not integrated into metropolitan regions. The HCC lethality rate remained relatively stable in both sexes, ranging from 21% to 25% (19%), but it was higher among older patients. The length of hospital stay did not differ between survivors and nonsurvivors throughout the study period. HCC hospitalizations are rising, particularly above 50 years of age and in rural areas, not paralleled by lethality rates. This suggests ongoing changes in environmental and socioeconomic factors in Brazil.
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Affiliation(s)
- Elizabeth Balbi
- D’Or Institute for Research and Education (IDOR), Botafogo, Rio de Janeiro 22281-100, Brazil
- Quinta D’Or Hospital, São Cristóvão, Rio de Janeiro 20941-150, Brazil
| | | | - Ronir Raggio Luiz
- Institute of Collective Health Studies (IESC), Federal University of Rio de Janeiro, Rio de Janeiro 21944-970, Brazil
| | - Renata de Mello Perez
- D’Or Institute for Research and Education (IDOR), Botafogo, Rio de Janeiro 22281-100, Brazil
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- D’Or Institute for Research and Education (IDOR), Botafogo, Rio de Janeiro 22281-100, Brazil
- Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil
- * Correspondence: Heitor SP de Souza, Department of Clinical Medicine, University Hospital, Federal University of Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco 255, Rio de Janeiro, RJ 21941-913, Brazil (e-mail: )
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33
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Tian Z, Xu C, Yang P, Lin Z, Wu W, Zhang W, Ding J, Ding R, Zhang X, Dou K. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Front Immunol 2022; 13:984728. [PMID: 36189208 PMCID: PMC9520190 DOI: 10.3389/fimmu.2022.984728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
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Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Peijun Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenlong Wu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
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Shiha G, Soliman R, Mikhail NNH, Carrat F, Azzi J, Nathalie GC, Toyoda H, Uojima H, Nozaki A, Takaguchi K, Hiraoka A, Atsukawa M, Abe H, Matsuura K, Mikami S, Watanabe T, Tsuji K, Ishikawa T, Suri V, Osinusi A, Ni L, Zou J, Sarin SK, Kumar M, Jalal PK, Hashim MA, Hassan M, Lopez SA, Bañares R, Ahumada AM, Mousa NH, Eslam M, Waked I. International multicenter validation of GES score for HCC risk stratification in chronic hepatitis C patients. J Viral Hepat 2022; 29:807-816. [PMID: 35657138 DOI: 10.1111/jvh.13717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/15/2022] [Accepted: 04/03/2022] [Indexed: 12/28/2022]
Abstract
We have recently demonstrated the ability of a simple predictive model (GES) score to determine the risk of hepatocellular carcinoma (HCC) after using direct-acting antivirals. However, our results were restricted to Egyptian patients with hepatitis C virus (HCV) genotype 4. Therefore, we studied a large, independent cohort of multiethnic populations through our international collaborative activity. Depending on their GES scores, patients are stratified into low risk (≤ 6/12.5), intermediate risk (> 6-7.5/12.5), and high risk (> 7.5/12.5) for HCC. A total of 12,038 patients with chronic HCV were analyzed in this study, of whom 11,202 were recruited from 54 centers in France, Japan, India, the U.S., and Spain, and the remaining 836 were selected from the Gilead-sponsored randomized controlled trial conducted across the U.S., Europe, Canada, and Australia. Descriptive statistics and log-rank tests. The performance of the GES score was evaluated using Harrell's C-index (HCI). The GES score proved successful at stratifying all patients into 3 risk groups, namely low-risk, intermediate-risk, and high-risk. It also displayed significant predictive value for HCC development in all participants (p < .0001), with HCI ranging from 0.55 to 0.76 among all cohorts after adjusting for HCV genotypes and patient ethnicities. The GES score can be used to stratify HCV patients into 3 categories of risk for HCC, namely low-risk, intermediate-risk, and high-risk, irrespective of their ethnicities or HCV genotypes. This international multicenter validation may allow the use of GES score in individualized HCC risk-based surveillance programs.
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Affiliation(s)
- Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), El Mansoura, Egypt
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), El Mansoura, Egypt
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Fuad, Egypt
| | - Nabiel N H Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), El Mansoura, Egypt
- Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Asyut, Egypt
| | - Fabrice Carrat
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
- AP-HP, Sorbonne Université, Hôpital Saint-Antoine, Santé Publique, Paris, France
| | - Jessica Azzi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | - Ganne-Carrié Nathalie
- APHP, Liver Unit, AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, Bobigny, France
- Université Sorbonne Paris Nord, Bobigny, France
- Inserm, UMR-1138 « Functional Genomics of solid tumors », Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akito Nozaki
- Gastroenterology Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Abe
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatusdo Central General Hospital, Matsudo, Japan
| | - Kentaro Matsuura
- Department of Virology & Liver Unit, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Noda, Japan
| | - Tsunamasa Watanabe
- Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kunihiko Tsuji
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Hepatology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Vithika Suri
- Gilead Sciences, Inc, Foster City, California, USA
| | - Anu Osinusi
- Gilead Sciences, Inc, Foster City, California, USA
| | - Liyun Ni
- Gilead Sciences, Inc, Foster City, California, USA
| | - Jun Zou
- Gilead Sciences, Inc, Foster City, California, USA
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Prasun Kumar Jalal
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA
| | - Mahmoud A Hashim
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA
| | - Manal Hassan
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA
- Department of Epidemiology, Division of Cancer Prevention and Population Sciences, MD Anderson, Houston, Texas, USA
| | - Sonia Alonso Lopez
- Liver Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain
- Instituto De Investigación SanitariaGregorio Marañón (IiSGM), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Rafael Bañares
- Liver Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain
- Instituto De Investigación SanitariaGregorio Marañón (IiSGM), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Adriana M Ahumada
- Liver Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain
| | - Nasser Hamed Mousa
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
| | - Imam Waked
- Hepatology Department, National Liver Institute, Menoufia University, Shebeen El-Kom, Egypt
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Mita E, Liu LJ, Shing D, Force L, Aoki K, Nakamoto D, Ishizaki A, Konishi H, Mizutani H, Ng LJ. Real-world Safety and Effectiveness of 24-week Sofosbuvir and Ribavirin Treatment in Patients Infected with Rare Chronic Hepatitis C Virus Genotypes 3, 4, 5, or 6 in Japan. Intern Med 2022; 62:1405-1414. [PMID: 36047126 DOI: 10.2169/internalmedicine.0067-22] [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] [Indexed: 11/06/2022] Open
Abstract
Objectives Real-world evidence on the safety and effectiveness of direct-acting antivirals in patients infected with chronic hepatitis C virus (HCV) genotypes (GTs) 3, 4, 5, or 6 in Japan is limited. This prospective observational study assesses the real-world safety profile and treatment effectiveness among patients prescribed sofosbuvir with ribavirin (SOF+RBV) for HCV GT3-6 infection in Japan. Methods Adults receiving 24-week SOF+RBV treatment for HCV GT3-6 infection were prospectively enrolled and observed through 24 weeks post-treatment for treatment-emergent adverse events (AEs) considered related to SOF and/or RBV by treating physicians and for a sustained virologic response at 12 and 24 weeks post-treatment (SVR12, SVR24). Incidence rates of related AEs and serious AEs (SAEs) were calculated. Proportions of patients experiencing related AEs/SAEs and those achieving SVR12 and SVR24 were assessed overall and by baseline characteristics, including treatment experience and cirrhosis status. Results Among the 50 patients included in the safety analysis, 92% had GT3 infection. The incidence rates of related AEs and SAEs were low overall (1.52 and 0.25 per 100 person-weeks, respectively), with 6.0% and 14.0% patients experiencing AEs related to SOF or RBV, respectively. There were no marked differences in the occurrence of related AEs/SAEs by patient baseline characteristics. SVR12 and SVR24 were achieved in 83.7% (41/49) and 82.2% (37/45) of patients, respectively. Lower effectiveness was observed among treatment-experienced patients and patients with cirrhosis at baseline. Conclusions This study demonstrated that SOF+RBV treatment for HCV GT3-6 infection was safe, effective, and an important treatment option for this difficult-to-treat patient population in Japan.
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Affiliation(s)
- Eiji Mita
- National Hospital Organization Osaka National Hospital, Japan
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Zajkowska M, Mroczko B. Chemokines in Primary Liver Cancer. Int J Mol Sci 2022; 23:ijms23168846. [PMID: 36012108 PMCID: PMC9408270 DOI: 10.3390/ijms23168846] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23158083. [PMID: 35897659 PMCID: PMC9329836 DOI: 10.3390/ijms23158083] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.
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Loo JH, Xu WXF, Low JT, Tay WX, Ang LS, Tam YC, Thurairajah PH, Kumar R, Wong YJ. Efficacy and safety of sofosbuvir/velpatasvir with or without ribavirin in hepatitis C genotype 3 compensated cirrhosis: A meta-analysis. World J Hepatol 2022; 14:1248-1257. [PMID: 35978662 PMCID: PMC9258247 DOI: 10.4254/wjh.v14.i6.1248] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 11/18/2021] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) is a leading cause of liver cirrhosis and hepatocellular carcinoma globally. Sofosbuvir/velpatasvir (SOF/VEL) is an effective pan-genotypic direct-acting antiviral combination for treatment of chronic HCV infection. While the addition of ribavirin (RBV) to SOF/VEL improved sustained virological response (SVR12) in genotype 3 (GT3) decompensated cirrhosis patients, the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear. AIM To evaluate the efficacy and safety of SOF/VEL, with or without RBV in GT3 compensated cirrhosis patients. METHODS We searched four electronic databases (PubMed/Medline, Embase, Cochrane Library and Web of Science) from inception up to June 2021 using both free text and MeSH terms. There was no restriction on language, geography, publication dates and publication status (full text or abstracts). All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL, with or without RBV, were included, regardless of age, gender or prior treatment experience. The primary outcome was sustained virological response 12-wk post-treatment (SVR12). The secondary outcome was treatment-related adverse events, as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL. The pooled relative risk (RR), 95%CI and heterogeneity (I 2) were estimated using Review Manager version 5.3. RESULTS From 1752 citations, a total of seven studies (2 randomized controlled trials, 5 cohort studies) with 1088 subjects were identified. The SVR12 was similar in GT3 compensated cirrhosis patients, regardless of the use of RBV, for both the intention-to-treat RR 1.03, 95%CI: 0.99-1.07; I 2 = 0%) and the per-protocol analysis (RR: 1.03, 95%CI: 0.99-1.07; I 2 = 48%). The overall pooled rate of treatment-related adverse events was 7.2%. Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL (RR: 4.20, 95%CI: 1.29-13.68; I 2 = 0%). Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions. However, addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients. CONCLUSION Ribavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL. Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.
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Affiliation(s)
- Jing Hong Loo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Wen Xin Flora Xu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Jun Teck Low
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Wei Xuan Tay
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Le Shaun Ang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Yew Chong Tam
- Education Resource Center, Medical Board, Singapore General Hospital, Singapore 100059, Singapore
| | - Prem Harichander Thurairajah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
- Department of Gastroenterology and Hepatology, National University Hospital, Singapore 119077, Singapore
| | - Rahul Kumar
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
- Duke-NUS Medicine Academic Clinical Program, Singapore 100059, Singapore
| | - Yu Jun Wong
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
- Duke-NUS Medicine Academic Clinical Program, Singapore 100059, Singapore.
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Direct-Acting Antiviral Agents for Hepatitis C Virus Infection-From Drug Discovery to Successful Implementation in Clinical Practice. Viruses 2022; 14:v14061325. [PMID: 35746796 PMCID: PMC9231290 DOI: 10.3390/v14061325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/13/2022] Open
Abstract
Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met.
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Liu X, Chen Z, Tang Q, Hu P. Phylogenetic signature and prevalence of natural resistance-associated substitutions for hepatitis C virus genotypes 3a and 3b in southwestern China. J Virus Erad 2022; 8:100071. [PMID: 35757658 PMCID: PMC9218835 DOI: 10.1016/j.jve.2022.100071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 03/01/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022] Open
Abstract
Background Patients infected with hepatitis C (HCV) genotype (GT) 3, especially GT3b, are still difficult to cure. GT3b is more common than GT3a in southwestern China. Here we aimed to investigate the prevalence of naturally occurring RASs in HCV GT3 in southwestern China and performed phylogenetic analysis. Methods Serum samples were collected from patients with HCV GT3 infection. Sanger sequencing was used to validate resistance-associated substitutions (RASs). Phylogenetic analysis was performed using MEGA X and the observed-minus-expected-squared algorithm was used to analyze amino acid covariance. Results A total of 136 patients were enrolled, including 41 HCV GT3a and 95 GT3b infected patients. In the NS5A region, the proportion of RASs found in GT3b (99%) was notably higher than in GT3a (9%). In the NS3 region, RASs prevalence in GT3b (5%) was lower than in GT3a (24%). NS5B-specific RASs were rare. Both the NS5A30k and L31 M substitutions occurred in 96% of GT3b sequences. The A30K + L31M combination was found in 94% of GT3b isolates, however, there were no A30K or L31M mutations observed in the GT3a sequence. Conclusions Significant differences were observed between HCV GT3a and GT3b in terms of RAS prevalence. The origin of GT3a appears to be more diverse compared with GT3b in southern China. Studies specifically aimed at HCV GT3b infection should be initiated to gain more insight into this subtype.
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Affiliation(s)
| | | | | | - Peng Hu
- Corresponding author. Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.,
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Azzi J, Dorival C, Cagnot C, Fontaine H, Lusivika-Nzinga C, Leroy V, De Ledinghen V, Tran A, Zoulim F, Alric L, Gournay J, Bronowicki JP, Decaens T, Riachi G, Mikhail N, Soliman R, Shiha G, Pol S, Carrat F, Ganne-Carrié N. Prediction of hepatocellular carcinoma in Hepatitis C patients with advanced fibrosis after sustained virologic response. Clin Res Hepatol Gastroenterol 2022; 46:101923. [PMID: 35405354 DOI: 10.1016/j.clinre.2022.101923] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/07/2022] [Accepted: 04/05/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS Prediction of hepatocellular carcinoma (HCC) occurrence in patients with chronic hepatitis C (HCV) who achieved a sustained virological response (SVR) after direct acting antivirals (DAAs) remains challenging. METHODS Among HCC-free HCV patients with advanced fibrosis enrolled in the ANRS CO22 HEPATHER cohort who achieved SVR 12 weeks after treatment with DAAs, HCC predictive models were developed using Cox multivariable regression. The derived score was externally validated in a large Egyptian cohort. Our main outcome was the HCC-free survival. RESULTS During follow-up (median 3.05 years), 153 out of 3531 patients developed a HCC. Main variables associated with HCC occurrence were: male gender, HCV genotype 3, esophageal varices, albumin < 40 g/L, total bilirubin >11 µmol/L and hypercholesterolemia before DAA initiation, together with age > 58 years, FIB-4 index ≥3.25 evaluated at SVR. A score was established allowing the stratification of patients by high (score ≥ 12/22), intermediate (7 ≤ score <12) and low risk of HCC (score < 7/22) with 3-yrs HCC incidence of 18.96%, 5.50% and 1.65%, respectively. The integrated time-dependent area under the ROC curve (i-AUC) was 0.76 in our patients and 0.61 in the validation cohort. CONCLUSION The externally validated HEPATHER HCC score has good short-term predictive performance in HCV- patients who achieved SVR12 after DAAs allowing to identify high-risk patients in whom HCC screening may be cost-effective and low-risk patients in whom HCC screening may be superfluous in the first 3 years after SVR.
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Affiliation(s)
- Jessica Azzi
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Céline Dorival
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Carole Cagnot
- ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), Unit for Basic and Clinical Research on Viral Hepatitis, Paris, France
| | | | - Clovis Lusivika-Nzinga
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Vincent Leroy
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France
| | - Victor De Ledinghen
- Hepatology Unit Hôpital Haut-Lévêque, Pessac, INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | - Albert Tran
- Université Côte d'Azur, Nice, France; CHU de Nice, Digestive Center, Nice, France; INSERM, U1065, C3M, Team 8 « Chronic liver diseases associated with obesity and alcohol », Nice, France
| | - Fabien Zoulim
- Department of Hepatology, Hospices Civils de Lyon, INSERM U1052, Université de Lyon, Lyon, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, France
| | - Jérôme Gournay
- Gastroenterology and Hepatology Department, Institut des Maladies de l'Appareil Digestif, University Hospital of Nantes, Nantes, France
| | - Jean-Pierre Bronowicki
- Inserm U1254 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Thomas Decaens
- Department of Hepatology and Gastroenterology, CHU Grenoble-Alpes, Université Grenoble-Alpes, Institute for Advanced Biosciences INSERM U1209, Grenoble, France
| | - Ghassan Riachi
- Department of Hepatology and Gastroenterology, CHU Charles Nicolle, Rouen, France
| | - Nabiel Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt; Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Assuit, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt; Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt; Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Stanislas Pol
- AP-HP, Hôpital Cochin, Unité d'Hépatologie, Paris, France; Université de Paris, INSERM U1223 and USM-20, Institut Pasteur, Paris, France
| | - Fabrice Carrat
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; AP-HP, Sorbonne Université, Hôpital Saint-Antoine, Santé Publique, Paris, France
| | - Nathalie Ganne-Carrié
- AP-HP, Hôpitaux Universitaires Paris Seine Saint-Denis, APHP, Liver Unit, Bobigny, France; Université Sorbonne Paris Nord, Bobigny, France; Inserm, UMR-1138 « Functional Genomics of solid tumors », Centre de Recherche des Cordeliers, Université de Paris, France.
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Hanif FM, Majid Z, Luck NH, Tasneem AA, Laeeq SM, Mubarak M. Revolution in the diagnosis and management of hepatitis C virus infection in current era. World J Hepatol 2022; 14:647-669. [PMID: 35646260 PMCID: PMC9099099 DOI: 10.4254/wjh.v14.i4.647] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 02/05/2022] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major global public health problem, particularly in developing part of the world. Significant advances have been made in the early diagnosis and treatment of the disease. Its management has been particularly revolutionized during the past two decades. In this review, we summarize the major advances in the diagnostic and management armamentarium for chronic HCV infection. The focus of the present review is on the newer directly acting anti-viral agents, which have revolutionized the management of chronic HCV infection. Management of uncomplicated chronic HCV infection and of specific complications and special at-risk populations of patients will be covered in detail. Despite the advent and approval of highly effective and well tolerable oral agents, still many challenges remain, particularly the affordability, the equitable distribution and access to later drugs. The World Health Organization aims to eliminate viral hepatitis including HCV by 2030 since its poses a major public health threat. There is an urgent need to ensure uniform and early access to diagnostic and therapeutic facilities throughout the world if the later goal has to be realized.
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Affiliation(s)
- Farina M Hanif
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Zain Majid
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Nasir Hassan Luck
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Abbas Ali Tasneem
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Syed Muddasir Laeeq
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation , Karachi 74200, Sindh, Pakistan.
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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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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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Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis. Sci Rep 2022; 12:5562. [PMID: 35365728 PMCID: PMC8975940 DOI: 10.1038/s41598-022-09588-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 03/22/2022] [Indexed: 01/04/2023] Open
Abstract
Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.
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Elsheikh MEA, McClure CP, Tarr AW, Irving WL. Sero-reactivity to three distinct regions within the hepatitis C virus alternative reading frame protein (ARFP/core+1) in patients with chronic HCV genotype-3 infection. J Gen Virol 2022; 103:001727. [PMID: 35230930 PMCID: PMC9176264 DOI: 10.1099/jgv.0.001727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Hepatitis C virus (HCV) infection affects more than 71 million people worldwide. The disease slowly progresses to chronic, long-term liver injury which leads to hepatocellular carcinoma (HCC) in 5 % of infections. The alternative reading frame protein (ARFP/core+1) is encoded by a sequence overlapping the HCV core gene in the +1 reading frame. Its role in hepatitis C pathogenesis and the viral life cycle is unclear, although some observers have related its production to disease progression and the development of HCC. The aim of this study was to determine whether ARFP is immunogenic in patients with chronic HCV genotype 3 infection and to assess whether sero-reactivity is associated with disease progression, particularly to HCC. Immunogenic epitopes within the protein were predicted by a bioinformatics tool, and three -20 aa length-peptides (ARFP-P1, ARFP-P2 and ARFP-P3) were synthesized and used in an avidin-biotin ARFP/core+1 peptide ELISA. Serum samples from 50 patients with chronic HCV genotype 3 infection, 50 genotype-1 patients, 50 HBV patients and 110 healthy controls were tested. Sero-reactivity to the ARFP peptides was also tested and compared in 114 chronic HCV genotype-3 patients subdivided on the basis of disease severity into non-cirrhotic, cirrhotic and HCC groups. Chronic HCV genotype-3 patients showed noticeable rates of reactivity to ARFP and core peptides. Seropositivity rates were 58% for ARFP-P1, 47 % for ARFP-P2, 5.9 % for ARFP-P3 and 100 % for C22 peptides. There was no significant difference between these seroreactivities between HCV genotype-3 patients with HCC, and HCV genotype-3 patients with and without liver cirrhosis. Patients with chronic HCV genotype-3 infection frequently produce antibodies against ARFP/core+1 protein. ARFP peptide reactivity was not associated with disease severity in patients with HCV genotype-3. These results support the conclusion that ARFP/core+1 is produced during HCV infection, but they do not confirm that antibodies to ARFP can indicate HCV disease progression.
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Affiliation(s)
- Mosaab E A Elsheikh
- School of Life Sciences, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, UK
| | - C Patrick McClure
- School of Life Sciences, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, UK.,Wolfson Centre for Global Virus Infections, The University of Nottingham, Nottingham, UK
| | - Alexander W Tarr
- School of Life Sciences, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, UK.,Wolfson Centre for Global Virus Infections, The University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - William L Irving
- School of Life Sciences, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, UK.,Wolfson Centre for Global Virus Infections, The University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
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Shiha G, Mikhail NNH, Soliman R, Hassan A, Eslam M. Predictive performance and clinical utility of HCC risk scores in chronic hepatitis C: a comparative study. Hepatol Int 2022; 16:159-170. [PMID: 35034266 DOI: 10.1007/s12072-021-10284-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Many HCC risk prediction scores were developed to guide HCC risk stratification and identify CHC patients who either need intensified surveillance or may not require screening. There is a need to compare different scores and their predictive performance in clinical practice. We aim to compare the newest HCC risk scores evaluating their discriminative ability, and clinical utility in a large cohort of CHC patients. PATIENTS AND METHODS The performance of the scores was evaluated in 3075 CHC patients who achieved SVR following DAAs using Log rank, Harrell's c statistic, also tested for HCC-risk stratification and negative predictive values. RESULTS HCC developed in 212 patients within 5 years follow-up. Twelve HCC risk scores were identified and displayed significant Log rank (p ≤ 0.05) except Alonso-Lopez TE-HCC, and Chun scores (p = 0.374, p = 0.053, respectively). Analysis of the remaining ten scores revealed that ADRES, GES pre-post treatment, GES algorithm and Watanabe (post-treatment) scores including dynamics of AFP, were clinically applicable and demonstrated good statistical performance; Log rank analysis < 0.001, Harrell's C statistic (0.66-0.83) and high negative predictive values (94.38-97.65%). In these three scores, the 5 years cumulative IR in low risk groups be very low (0.54-1.6), so screening could be avoided safely in these patients. CONCLUSION ADRES, GES (pre- and post-treatment), GES algorithm and Watanabe (post-treatment) scores seem to offer acceptable HCC-risk predictability and clinical utility in CHC patients. The dynamics of AFP as a component of these scores may explain their high performance when compared to other scores.
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Affiliation(s)
- Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt.
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Nabiel N H Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt
- Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Reham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Ayman Hassan
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, Mansoura, Egypt
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
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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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Kadiri DD, Peela S, Ganguli D. Effect of cirrhosis and hepatitis on the prognosis of liver cancer. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:51-72. [DOI: 10.1016/b978-0-323-98806-3.00002-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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50
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Immune System Disorders, Cancer and Viral Infections: A New Treatment Opportunity for the Immune Checkpoint Inhibitors. Life (Basel) 2021; 11:life11121400. [PMID: 34947931 PMCID: PMC8709484 DOI: 10.3390/life11121400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 11/26/2022] Open
Abstract
The relationship between viral infections and cancer is well known and has been established for decades. Multiple tumours are generated from alterations secondary to viral infections 2 resulting from a dysregulation of the immune system in many cases. Certain causal relationships, such as that between the Epstein–Barr virus (EBV) in nasopharyngeal cancer or hepatitis C and B viruses in hepatocarcinoma, have been clearly established, and their implications for the prognosis and treatment of solid tumours are currently unknown. Multiple studies have evaluated the role that these infections may have in the treatment of solid tumours using immunotherapy. A possible relationship between viral infections and an increased response to immune checkpoint inhibitors (ICIs) has been established at a theoretical level in solid neoplasms, such as EBV-positive cavum cancer and human papillomavirus (HPV)-positive and oropharyngeal cancer. These could yield a greater response associated with the activation of the immune system secondary to viral infection, the consequence of which is an increase in survival in these patients. That is why the objective of this review is to assess the different studies or clinical trials carried out in patients with solid tumours secondary to viral infections and their relationship to the response to ICIs.
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