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Millian DE, Arroyave E, Wanninger TG, Krishnan S, Bao D, Zhang JR, Rao A, Spratt H, Ferguson M, Chen V, Stevenson HL, Saldarriaga OA. Alterations in the hepatic microenvironment following direct-acting antiviral therapy for chronic hepatitis C. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.17.25321289. [PMID: 40034770 PMCID: PMC11875275 DOI: 10.1101/2025.02.17.25321289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Background and aims. The first direct-acting antivirals (DAAs) to treat the viral hepatitis C (HCV) became available in 2011. Despite numerous clinical studies of patient outcomes after treatment, few have evaluated changes in the liver microenvironment. Despite achieving sustained virologic response (SVR), patients may still experience adverse outcomes like cirrhosis and hepatocellular carcinoma. By comparing gene and protein expression in liver biopsies collected before and after treatment, we sought to determine whether specific signatures correlated with disease progression and adverse clinical outcomes. Methods. Biopsies were collected from 22 patients before and after DAA treatment. We measured ∼770 genes and used multispectral imaging with custom machine learning algorithms to analyze phenotypes of intrahepatic macrophages (CD68, CD14, CD16, MAC387, CD163) and T cells (CD3, CD4, CD8, CD45, FoxP3). Results. Before DAA treatment, patients showed two distinct gene expression patterns: one with high pro-inflammatory and antiviral gene expression and another with weaker expression. Patients with adverse outcomes exhibited significantly (p<0.05) more inflammatory activity and had more advanced fibrosis stages in their baseline biopsies than those with liver disease resolution. Patients who achieved SVR had significantly decreased liver enzymes, reduced inflammatory scores, and restored type 1 interferon pathways similar to controls. However, after DAA treatment, patients with persistently high gene expression (67%, pre-hot) still had significantly worse outcomes (p<0.049) despite achieving SVR. A persistent lymphocytic infiltrate was observed in a subset of these patients (76.5%). After therapy, anti-inflammatory macrophages (CD16+, CD16+CD163+, CD16+CD68+) increased, and T cell heterogeneity was more pronounced, showing a predominance of helper and memory T cells (CD3+CD45RO+, CD4+CD45RO+, CD3+CD4+CD45RO+). Conclusions. Patients who have more inflamed livers and more advanced fibrosis before DAA treatment should be closely followed for the development of adverse outcomes, even after achieving SVR. We can enhance patient risk stratification by integrating gene and protein expression profiles with clinical data. This could identify those who may benefit from more intensive monitoring or alternative therapeutic approaches, inspiring a new era of personalized patient care. Lay Summary Direct-acting antiviral (DAA) therapy has dramatically improved the treatment of chronic HCV, making it curable for most people. This study determined gene and protein expression differences in the liver before and after treatment of HCV. These results will lead to a deeper understanding of the changes in the hepatic immune microenvironment with and without the virus present in the liver in hopes of improving patient surveillance, prognosis, and outcome in the future.
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Zheng J, Lin J, Ma Y, Yang C, Zhong Q, Li Y, Yang Q. Establishment of sheep nasal mucosa explant model and its application in antiviral research. Front Microbiol 2023; 14:1124936. [PMID: 37256060 PMCID: PMC10226428 DOI: 10.3389/fmicb.2023.1124936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/18/2023] [Indexed: 06/01/2023] Open
Abstract
The nasal mucosa is the first barrier to pathogen invasion through the respiratory tract. Few studies have focused on nasal resistance to invasion by respiratory pathogens due to the lack of models related to the nasal mucosa. Hence, it is necessary to construct a nasal mucosal model to study host-pathogen interactions. We established a long-term in vitro sheep nasal mucosa explant model (NMEM), which exhibited typical epithelial cilia and epithelial proliferation ability within 11 days. Moreover, to evaluate whether the NMEM was suited for in vitro pathogenic study, we used pseudorabies virus (PRV) and showed that it successfully infected and produced severe lesions in the NMEM, particularly interferon (IFN)-stimulated gene product 15 (ISG15). IFN decreased significantly after the PRV infection. Similarly, we used this NMEM model to screen several antiviral substances, such as probiotics and drugs. A previous study showed that nasal commensal bacteria, particularly Bacillus subtilis, had high antiviral activity. Then, we used the NMEM to evaluate six sheep-derived B. subtilis strains and demonstrated that it significantly induced the production of IFN and expression of ISG15. The sheep-derived B. subtilis was pretreated with the sheep NMEM before the PRV infection to evaluate the antiviral effect. The results showed that NSV2 significantly inhibited infection by PRV and reduced the viral load (p < 0.05). Furthermore, NSV2 may inhibit PRV replication by enhancing ISGylation of cells. In conclusion, we established a reliable in vitro culture model of sheep NMEM, and applied it in antiviral research.
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Tao R, Han M, Yuan W, Xiao F, Huang J, Wang X, Luo X, Yan W, Wan X, Ning Q. Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis. Int Immunopharmacol 2023; 117:109631. [PMID: 36878044 DOI: 10.1016/j.intimp.2022.109631] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/08/2022] [Accepted: 12/20/2022] [Indexed: 03/07/2023]
Abstract
Fibrinogen-like protein 2 (Fgl2) robustly activates macrophages in response to infection or inflammatory cytokine challenge and is markedly increased in the liver tissues of liver cirrhosis patientswithhepatitisCvirus(HCV) infection. However, the molecular mechanism underlying the involvement of Fgl2 in macrophage function in the pathogenesis of liver fibrosis remains unclear. In this study, we demonstrated that increased hepatic Fgl2 expression was associated with hepatic inflammation and high-grade liver fibrosis in patients with hepatitis B virus (HBV) infection and experimental models. Genetic ablation of Fgl2 alleviated hepatic inflammation and fibrosis progression. Fgl2 promoted M1 macrophage polarization and increased the production of proinflammatory cytokines that contribute to inflammatory damage and fibrosis development. In addition, Fgl2 augmented mitochondrial reactive oxygen species (ROS) production and modulated mitochondrial functions. Fgl2-mediated mtROS were involved in macrophage activation and polarization. We further demonstrated that in macrophages, Fgl2 localized to not only the cytosol but also mitochondria, where it bound to cytosolic and mitochondrial heat shock protein 90 (HSP90). Mechanistically, Fgl2 interacted with HSP90, hindering the interaction of HSP90 with its target protein Akt, significantly inhibiting Akt phosphorylation and downstream FoxO1 phosphorylation. These results reveal different layers of regulation of Fgl2 that are necessary for inflammatory damage and mitochondrial dysfunction in M1-polarized macrophages. Therefore, Fgl2 may be a potent target in liver fibrosis treatment.
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Affiliation(s)
- Ran Tao
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Meiwen Han
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Yuan
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fang Xiao
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiaquan Huang
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaojing Wang
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Weiming Yan
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xiaoyang Wan
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Qin Ning
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Cossiga V, La Civita E, Bruzzese D, Guarino M, Fiorentino A, Sorrentino R, Pontillo G, Vallefuoco L, Brusa S, Montella E, Terracciano D, Morisco F, Portella G. Enhanced liver fibrosis score as a noninvasive biomarker in hepatitis C virus patients after direct-acting antiviral agents. Front Pharmacol 2022; 13:891398. [PMID: 36059971 PMCID: PMC9428144 DOI: 10.3389/fphar.2022.891398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background: In more than 90% of chronic viral hepatitis C (HCV) patients treated with direct-acting antiviral agents (DAAs), a sustained viral response (SVR) was observed. Unfortunately, there are subgroups of subjects who display enduring liver fibrosis and are at high risk of developing hepatocellular carcinoma (HCC). Thus, liver fibrosis evaluation during the follow-up of these patients plays a pivotal role. The gold standard to evaluate hepatic fibrosis is liver biopsy, which is an invasive procedure. Imaging techniques and serum biomarkers have been proposed as safer and cheaper procedures. Objectives: In this study, we evaluated the concordance of transient elastography (TE) with ELF score ( enhanced liver fibrosis) in a cohort of patients with HCV before and after direct-acting antiviral (DAAs) treatment. ELF score has been validated in other chronic liver diseases; the evidence is not available in HCV patients treated with DAAs. Study design: We prospectively recruited all consecutive HCV patient candidates for DAAs therapy at the University of Naples “Federico II” between April 2015 and July 2016. TE and ELF scores were assessed at baseline, at SVR24, and at SVR48. Results: One-hundred-nineteen patients were treated with DAAs, and 94.1% of them reached SVR. A total of 55.5% of patients were males with a mean age of 64.7 ± 9.6 years. TE results revealed that 12 patients (10%) had F1-2 mild/moderate fibrosis, and 107 (90%) had F3-4 advanced fibrosis. At baseline, SVR24, and SVR48, the concordance between ELF test and TE was poor: 0.11 (p = 0.086), 0.15 (p = 0.124), and 0.034 (p = 0.002), respectively. However, at SVR24 and SVR48, both methods showed a significant amelioration of liver fibrosis compared to baseline (p < 0.001). In addition, both ELF index and TE were significantly associated with portal hypertension at baseline, but not with varices and ascites. Conclusions: Our findings suggested that ELF test could predict changes in liver fibrosis, independently of TE. In case of TE unavailability, ELF score could represent an appropriate tool. Notably, in the context of the COVID-19 pandemic, ELF testing should be encouraged to reduce unnecessary access to the hospital and prolonged physical contact.
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Affiliation(s)
- Valentina Cossiga
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
- *Correspondence: Daniela Terracciano, ; Valentina Cossiga,
| | - Evelina La Civita
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
| | - Dario Bruzzese
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
| | - Andrea Fiorentino
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
| | - Rosanna Sorrentino
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
| | - Giuseppina Pontillo
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
| | - Luca Vallefuoco
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
| | - Stefano Brusa
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
| | - Emma Montella
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Daniela Terracciano
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
- *Correspondence: Daniela Terracciano, ; Valentina Cossiga,
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
| | - Giuseppe Portella
- Department of Translational Medical Science, University of Naples “Federico II”, Naples, Italy
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Wallace HL, Wang L, Gardner CL, Corkum CP, Grant MD, Hirasawa K, Russell RS. Crosstalk Between Pyroptosis and Apoptosis in Hepatitis C Virus-induced Cell Death. Front Immunol 2022; 13:788138. [PMID: 35237259 PMCID: PMC8882739 DOI: 10.3389/fimmu.2022.788138] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/10/2022] [Indexed: 01/15/2023] Open
Abstract
Extensive inflammation in the liver is known to contribute to the pathogenesis of hepatitis C virus (HCV) infection. Apoptosis has, for a long time, been known to act as a mechanism of hepatocyte death, but our previous research also identified inflammasome-mediated pyroptosis in infected and uninfected bystander cells as an additional mechanism of HCV-induced cytopathicity. The purpose of this study was to investigate the mechanism of HCV-induced cell death and to determine the timing and relative contributions of apoptosis and pyroptosis during HCV infection. In a model employing a cell culture-adapted strain of JFH-1 HCV and Huh-7.5 hepatocyte-like cells, we found that pyroptosis occurred earlier than did apoptosis during infection. CRISPR knockout of NLRP3 resulted in decreased caspase-1 activation, but not complete elimination, indicating multiple sensors are likely involved in HCV-induced pyroptosis. Knockout of gasdermin-D resulted in increased activation of apoptosis-related caspase-3, suggesting potential crosstalk between the two cell death pathways. An unexpected decrease in activated caspase-1 levels was observed when caspase-3 was knocked out, implying that caspase-3 may have a role in the initiation of pyroptosis, at least in the context of HCV infection. Lower viral titres in culture fluids and increased ratios of intracellular to extracellular levels of infectious virus were observed in knockout versus wild-type Huh-7.5 cells, suggesting that HCV may induce programmed cell death in order to enhance virus release from infected cells. These results contribute to the understanding of HCV pathogenesis and add to the increasing volume of literature suggesting various programmed cell death pathways are not mutually exclusive.
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Affiliation(s)
- Hannah L. Wallace
- Immunology and Infectious Diseases, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Lingyan Wang
- Immunology and Infectious Diseases, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Cassandra L. Gardner
- Immunology and Infectious Diseases, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Christopher P. Corkum
- Confocal Imaging/Flow Cytometry Unit, Medical Laboratories, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Michael D. Grant
- Immunology and Infectious Diseases, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Kensuke Hirasawa
- Immunology and Infectious Diseases, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - Rodney S. Russell
- Immunology and Infectious Diseases, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
- *Correspondence: Rodney S. Russell,
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Sanghi V, Romero-Marrero C, Flocco G, Graham RP, Abduljawad B, Niyazi F, Asfari MM, Hashimoto K, Eghtesad B, Menon KVN, Aucejo FN, Lopez R, Yerian LM, Allende DS. The spectrum of histopathological findings after SVR to DAA for recurrent HCV infection in liver transplant recipients. Virchows Arch 2021; 480:335-347. [PMID: 34498114 DOI: 10.1007/s00428-021-03191-6] [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: 05/14/2021] [Revised: 08/07/2021] [Accepted: 08/17/2021] [Indexed: 10/20/2022]
Abstract
Sustained virological response (SVR) to the treatment of recurrent HCV in liver transplant recipients has excellent clinical outcomes; however, little is known about the effects on allograft histology. The study aimed to assess the histology of the allograft liver. In this single-center, retrospective cohort study, patients with recurrent hepatitis C (HCV) in allograft liver who were cured with antiviral therapy between 2010 and 2016 were identified. Biopsies were reviewed by two liver pathologists blinded to the treatment and SVR status. Paired analysis was performed to compare pre- and post-treatment histological features. Of the 62 patients analyzed, 22 patients received PEGylated interferon/ribavirin (IFN) therapy, while 40 patients received direct-acting antiviral agents (DAA). The mean age was 57 years, 24% were female, and 79% were Caucasian. RNA in situ hybridization testing for HCV and HEV was negative in all the tested patients. Significant reduction in the inflammatory grade of post-treatment biopsy specimens was noted in all subjects (n = 57; p < 0.001) and in the IFN group (n = 21; p = 0.001) but not in the DAA group (p = 0.093). Of all subjects, 21% had worsening stage, 31% had improvement, and 48% had no change in stage. Of the treatment groups, 27% in the IFN and 17% in the DAA groups had worsening stage; however, the results were not statistically significant in all subjects or by treatment modality. Persistent inflammatory infiltrates and fibrosis was noted in allograft tissue of patients cured with DAA. Significant improvement in grade was noted in the IFN group, without a significant change in stage.
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Affiliation(s)
- Vedha Sanghi
- Department of Gastroenterology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Carlos Romero-Marrero
- Department of Gastroenterology and Hepatology, Memorial Healthcare System, Hollywood, FL, USA
| | - Gianina Flocco
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Rondell P Graham
- Department of Gastroenterology & Liver Pathology, Mayo Clinic, Rochester, MN, USA
| | - Baraa Abduljawad
- Department of Critical Care Medicine/Transplant Hepatology, Cleveland Clinic Foundation, Abu Dhabi, United Arab Emirates
| | - Fadi Niyazi
- Department of Gastroenterology, Hepatology and Nutrition, University of Iowa, Iowa City, IA, USA
| | - Mohammad M Asfari
- Department of Gastroenterology, Hepatology and Nutrition, Augusta University, Augusta, GA, USA
| | - Koji Hashimoto
- Department of Surgery - Liver Transplantation, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Bijan Eghtesad
- Department of Surgery - Liver Transplantation, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - K V Narayanan Menon
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Federico N Aucejo
- Department of Surgery - Liver Transplantation, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Rocio Lopez
- Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Lisa M Yerian
- Department of Gastrointestinal and Hepatobiliary Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Daniela S Allende
- Department of Gastrointestinal and Hepatobiliary Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.
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Herderschee J, Heinonen T, Fenwick C, Schrijver IT, Ohmiti K, Moradpour D, Cavassini M, Pantaleo G, Roger T, Calandra T. High-dimensional immune phenotyping of blood cells by mass cytometry in patients infected with hepatitis C virus. Clin Microbiol Infect 2021; 28:611.e1-611.e7. [PMID: 34474121 DOI: 10.1016/j.cmi.2021.08.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/18/2021] [Accepted: 08/21/2021] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV before and after DAA therapy. METHODS Before and 12 weeks after sustained virological response (SVR12) to DAA therapy, 22 cell populations were analysed by mass cytometry in blood collected from ten healthy control individuals and 20 HCV-infected patients with (ten patients) or without (ten patients) human immunodeficiency virus (HIV) infection. RESULTS HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies (median, interquartile range (IQR); control, HCV, HCV/HIV) of intermediate monocytes (1.2, IQR 0.47-1.46; 1.76, IQR 0.83-2.66; 0.78, IQR 0.28-1.77), non-classical monocytes (1.11, IQR 0.49-1.26; 0.9, IQR 0.18-0.99; 0.54, IQR 0.28-1.77), conventional dendritic cells type 2 (0.55, IQR 0.35-0.59; 0.31, IQR 0.16-0.38; 0.19, IQR 0.11-0.36) and CD56dim natural killer cells (8.08, IQR 5.34-9.79; 4.72, IQR 2.59-6.05) 3.61, IQR 2.98-5.07) were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells (0.07, IQR 0.06-0.10; 0.10, IQR 0.09-0.19; 0.19, IQR 0.12-0.25), activated CD4 T cells (0.28, IQR 0.21-0.36; 0.56, IQR 0.33-0.77; 0.40, IQR 0.22-0.53) and activated CD8 T cells (0.23, IQR 0.14-0.42; 0.74, IQR 0.30-1.65; 0.80, IQR 0.58-1.16) were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV- and HCV/HIV-infected patients, respectively. Most alterations persisted at SVR12. CONCLUSIONS Chronic HCV and HCV/HIV infections induce profound and durable perturbations of innate and adaptive immune homeostasis.
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Affiliation(s)
- Jacobus Herderschee
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Tytti Heinonen
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Craig Fenwick
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Irene T Schrijver
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Khalid Ohmiti
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Matthias Cavassini
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Giuseppe Pantaleo
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; Swiss Vaccine Research Institute, Lausanne, Switzerland
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thierry Calandra
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
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Saldarriaga OA, Dye B, Pham J, Wanninger TG, Millian D, Kueht M, Freiberg B, Utay N, Stevenson HL. Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome. Sci Rep 2021; 11:14506. [PMID: 34267267 PMCID: PMC8282660 DOI: 10.1038/s41598-021-93881-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.
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Affiliation(s)
- Omar A Saldarriaga
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Bradley Dye
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Judy Pham
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Timothy G Wanninger
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Daniel Millian
- School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Michael Kueht
- Dept. of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA
| | - Benjamin Freiberg
- Digital Pathology, Araceli Biosciences, 7425 NE Evergreen Pkwy, Hillsboro, OR, 97124, USA
| | - Netanya Utay
- Department of Internal Medicine, University of Texas Health Science Center at Houston, 7000 Fannin St # 1200, Houston, TX, 77030, USA
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0144, USA.
- Department of Pathology, The University of Texas Medical Branch, 712 Texas Avenue, Clinical Services Wing-Room 5.506Q, Galveston, TX, 77555-0416, USA.
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Peschel G, Grimm J, Buechler C, Gunckel M, Pollinger K, Aschenbrenner E, Kammerer S, Jung EM, Haimerl M, Werner J, Müller M, Weigand K. Liver stiffness assessed by shear-wave elastography declines in parallel with immunoregulatory proteins in patients with chronic HCV infection during DAA therapy. Clin Hemorheol Microcirc 2021; 79:541-555. [PMID: 34120896 DOI: 10.3233/ch-211193] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND A rapid decline of liver stiffness (LS) was detected by non-invasive methods in patients with chronic hepatitis C (HCV) infection during treatment with direct-acting antivirals (DAA). OBJECTIVE To investigate the influence of inflammation on LS. METHODS We prospectively examined LS by sonographic shear-wave elastography in 217 patients during DAA therapy from treatment initiation (BL) to 12 weeks after end of therapy (SVR12). Demographic data, laboratory findings and serum levels of cytokines were determined. RESULTS Values of LS decreased from 1.86 m/s to 1.68 m/s (p = 0.01) which was most pronounced in patients who had F4 fibrosis at BL (3.27 m/s to 2.37 m/s; p < 0.001). Initially elevated values of aminotransferases, ferritin, IgG (p < 0.001 each) and international normalized ratio (p < 0.003) declined, thrombocyte count (p = 0.007) increased. Correlations of these laboratory parameters with BL levels of LS measurement (LSM) were most apparent in patients with F1-F3 fibrosis. Tumor necrosis factor (TNF)-α (p = 0.031), interleukin (IL)-10 (p = 0.005) and interferon y inducible protein (IP)-10 (p < 0.001) decreased in parallel with LSM under DAA therapy and corelated with BL values. CONCLUSION Decrease of systemic inflammatory parameters correlated with LSM under DAA therapy. We conclude that regression of LSM is attributable to the decline of inflammation rather than reflecting fibrosis.
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Affiliation(s)
- G Peschel
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - J Grimm
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - C Buechler
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - M Gunckel
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - K Pollinger
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - E Aschenbrenner
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - S Kammerer
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - E M Jung
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - M Haimerl
- Department of Radiology, University Hospital Regensburg, Regensburg, Germany
| | - J Werner
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - M Müller
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
| | - K Weigand
- Department of Gastroenterology, Endocrinology, Rheumatology and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
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10
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Celli R, Saffo S, Kamili S, Wiese N, Hayden T, Taddei T, Jain D. Liver Pathologic Changes After Direct-Acting Antiviral Agent Therapy and Sustained Virologic Response in the Setting of Chronic Hepatitis C Virus Infection. Arch Pathol Lab Med 2021; 145:419-427. [PMID: 32810870 PMCID: PMC10960369 DOI: 10.5858/arpa.2020-0008-oa] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Treatment of chronic viral hepatitis C (HCV) infection with direct-acting antiviral agents (DAAs) results in cure, or sustained viral response (SVR), in more than 90% of patients. However, there are subsets of patients who have persistent liver inflammation and fibrosis and develop hepatocellular carcinoma (HCC) despite achieving SVR. A possible reason for these phenomena may be the presence of virus particles in liver tissue but not blood, otherwise defined as occult infection. OBJECTIVE.— To describe liver histologic findings following successful DAA therapy, test HCV RNA by (liver) tissue polymerase chain reaction in treated cases, and identify predictive markers for HCC development in treated cases. DESIGN.— A total of 96 identified patients were divided into 4 groups, each differentiated by the presence or absence of SVR and HCC. Groups were compared for several clinicopathologic variables, including degree of inflammation and fibrosis, and the 'directionality' of fibrosis in cirrhotic livers using the novel progressive-indeterminate-regressive scoring system. RESULTS.— Overall, we found a significant decrease in inflammation in SVR patients. None of the patients showed regression of their cirrhosis following treatment. No evidence of occult HCV infection was seen in 40 livers tested, including 21 with HCC. The number of patients who developed HCC was similar in the SVR and non-SVR groups, and increased inflammation and fibrosis were associated with HCC development. CONCLUSIONS.— Following DAA-SVR there appears to be an overall decrease in inflammation, but the fibrosis tends to persist, at least in the short term (median follow-up of 20.2 months).
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Affiliation(s)
- Romulo Celli
- Department of Pathology (Celli), Yale School of Medicine, New Haven, Connecticut
- Celli is currently with the Department of Pathology at Middlesex Health, Middletown, Connecticut
| | - Saad Saffo
- From the Section of Digestive Diseases, Department of Internal Medicine (Saffo, Taddei), Yale School of Medicine, New Haven, Connecticut
| | - Saleem Kamili
- the Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia (Kamili, Wiese, Hayden)
| | - Nicholas Wiese
- the Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia (Kamili, Wiese, Hayden)
| | - Tonya Hayden
- the Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia (Kamili, Wiese, Hayden)
| | - Tamar Taddei
- From the Section of Digestive Diseases, Department of Internal Medicine (Saffo, Taddei), Yale School of Medicine, New Haven, Connecticut
| | - Dhanpat Jain
- The Section of Gastrointestinal and Liver Pathology (Jain), Yale School of Medicine, New Haven, Connecticut
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11
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Huang R, Rao HY, Yang M, Gao YH, Wang J, Jin Q, Ma DL, Wei L. Histopathology and the predominantly progressive, indeterminate and predominately regressive score in hepatitis C virus patients after direct-acting antivirals therapy. World J Gastroenterol 2021; 27:404-415. [PMID: 33584072 PMCID: PMC7856841 DOI: 10.3748/wjg.v27.i5.404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/14/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Histological changes after direct-acting antivirals (DAAs) therapy in hepatitis C virus (HCV) patients has not been elucidated. Whether the predominantly progressive, indeterminate and predominately regressive (P-I-R) score, evaluating fibrosis activity in hepatitis B virus patients has predictive value in HCV patients has not been investigated.
AIM To identify histological changes after DAAs therapy and to evaluate the predictive value of the P-I-R score in HCV patients.
METHODS Chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. Sustained virologic response (SVR) was defined as an undetectable serum HCV RNA level at 24 wk after treatment cessation. The Ishak system and P-I-R score were assessed. Inflammation improvement and fibrosis regression were defined as a ≥ 2-points decrease in the histology activity index (HAI) score and a ≥ 1-point decrease in the Ishak fibrosis score, respectively. Fibrosis progression was defined as a ≥ 1-point increase in the Ishak fibrosis score. Histologic improvement was defined as a ≥ 2-points decrease in the HAI score without worsening of the Ishak fibrosis score after DAAs therapy. The P-I-R score was also assessed. “absolutely reversing or advancing” was defined as the same directionality implied by both change in the Ishak score and posttreatment P-I-R score; and “probably reversing or advancing” was defined as only one parameter showing directionality.
RESULTS Thirty-eight chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included. The mean age of these patients was 40.9 ± 14.6 years and there were 53% (20/38) males. Thirty-four percent (13/38) of patients were cirrhotic. Eighty-two percent (31/38) of patients achieved inflammation improvement. The median HAI score decreased significantly after SVR (pretreatment 7.0 vs posttreatment 2.0, Z = -5.146, P = 0.000). Thirty-seven percent (14/38) of patients achieved fibrosis improvement. The median Ishak score decreased significantly after SVR (pretreatment 4.0 vs posttreatment 3.0, Z = -2.354, P = 0.019). Eighty-two percent (31/38) of patients showed histological improvement. The P-I-R score was evaluated in 61% (23/38) of patients. The progressive group showed lower platelet (P = 0.024) and higher HAI scores (P = 0.070) before treatment. In patients with stable Ishak stage after treatment: Progressive injury was seen in 22% (4/18) of patients, 33% (6/18) were classified as indeterminate and regressive changes were seen in 44% (8/18) of patients who were judged as probably reversing by the Ishak and P-I-R systems.
CONCLUSION Significant improvement of necroinflammation and partial remission of fibrosis in HCV patients occurred shortly after DAAs therapy. The P-I-R score has potential in predicting fibrosis in HCV patients.
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Affiliation(s)
- Rui Huang
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Hui-Ying Rao
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Ming Yang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Ying-Hui Gao
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Jian Wang
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Qian Jin
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Dan-Li Ma
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University People’s Hospital, Beijing 100044, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
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12
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Enomoto M, Kawada N. The Moral of Hepatic Fibrosis: Don't Always Believe Noninvasive Fibrosis Measurements. Dig Dis Sci 2020; 65:1293-1295. [PMID: 31894483 DOI: 10.1007/s10620-019-06035-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno, Osaka, 545-8585, Japan.
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno, Osaka, 545-8585, Japan
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13
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Huang R, Rao H, Yang M, Gao Y, Wang J, Jin Q, Ma D, Wei L. Noninvasive Measurements Predict Liver Fibrosis Well in Hepatitis C Virus Patients After Direct-Acting Antiviral Therapy. Dig Dis Sci 2020; 65:1491-1500. [PMID: 31654313 DOI: 10.1007/s10620-019-05886-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 10/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Short-time usage of direct-acting antiviral agents (DAA) limited knowledge regarding histological outcomes and predictive values of noninvasive measurements in patients with hepatitis C virus (HCV) after sustained virologic response (SVR) with DAA. AIMS This study aimed to indicate histological changes and assess predictive value of noninvasive measurements for fibrosis in these patients. METHODS HCV patients who achieved SVR by DAA were identified. Pre- and post-SVR clinical and histological data were collected. RESULTS Of patients, 83% (33/40), 38% (15/40) and 83% (33/40) achieved inflammation improvement, fibrosis regression and histological improvement, respectively. Liver stiffness measurements (LSM), APRI, and FIB-4 could predict post-SVR fibrosis well without significant differences. Areas under receiver operating characteristic curves of LSM, APRI, and FIB-4 were 0.78, 0.81, and 0.87 for post-SVR advanced fibrosis (≥ F4) and 0.86, 0.86, and 0.85 for post-SVR cirrhosis (≥ F5), respectively. Pre-SVR LSM, APRI, and FIB-4 values were significantly lower in patients with fibrosis regression (P = 0.003-0.012), while FIB-4 was significantly lower in patients with histological improvement (P = 0.012-0.033). Patients with higher pre-SVR Ishak scores tended to have bigger decline in APRI (P = 0.025) and FIB-4 (P = 0.024) after SVR. CONCLUSIONS DAA could improve liver inflammation and fibrosis of HCV patients in a short time after SVR. LSM, APRI, and FIB-4 predict fibrosis well even after SVR by DAA. Most of the cutoff values for advanced fibrosis (≥ F4) and cirrhosis (≥ F5) of these noninvasive measurements decreased significantly after SVR, maybe because of the inflammation improvement.
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Affiliation(s)
- Rui Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Ming Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China.,Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yinghui Gao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Jian Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Qian Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Danli Ma
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, China. .,Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
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14
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Amaddeo G, Nguyen CT, Maillé P, Mulé S, Luciani A, Machou C, Rodrigues A, Regnault H, Mallat A, Laurent A, Lafdil F, Hézode C, Pawlotsky JM, Calderaro J. Intrahepatic immune changes after hepatitis c virus eradication by direct-acting antiviral therapy. Liver Int 2020; 40:74-82. [PMID: 31444947 DOI: 10.1111/liv.14226] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 08/15/2019] [Accepted: 08/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth. This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy. METHODS Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non-tumoral tissues and analysed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry. RESULTS Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients. CONCLUSION In conclusion, removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA-induced SVR.
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Affiliation(s)
- Giuliana Amaddeo
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service d'Hépatologie, Créteil, France
| | - Cong Trung Nguyen
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France
| | - Pascale Maillé
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France
| | - Sebastien Mulé
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service d'Imagerie Médicale, Créteil, France
| | - Alain Luciani
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service d'Imagerie Médicale, Créteil, France
| | - Camilia Machou
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France
| | - Aurélie Rodrigues
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France
| | - Hélène Regnault
- APHP, Groupe Hospitalier Henri Mondor, Service d'Hépatologie, Créteil, France
| | - Ariane Mallat
- Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service d'Hépatologie, Créteil, France
| | - Alexis Laurent
- Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service de Chirurgie Digestive et Hépatobiliaire, Créteil, France
| | - Fouad Lafdil
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France
| | - Christophe Hézode
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service d'Hépatologie, Créteil, France
| | - Jean-Michel Pawlotsky
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Service de Virologie, Bactériologie-Hygiène, Mycologie-Parasitologie et unité Transversale de Traitement des Infections, Centre National de Référence des Hépatites Virales B, C et Delta, Créteil, France
| | - Julien Calderaro
- INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.,Université Paris-Est Créteil, Créteil, France.,APHP, Groupe Hospitalier Henri Mondor, Département de Pathologie, Créteil, France
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15
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Putra J, Schiano TD, Fiel MI. Resolution of HCV-Autoimmune Hepatitis Overlap Syndrome With Antiviral TreatmentA Paired Liver Biopsy Study. Am J Clin Pathol 2019; 152:735-741. [PMID: 31310654 DOI: 10.1093/ajcp/aqz095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES To evaluate histologic changes occurring in patients having chronic hepatitis C and autoimmune hepatitis overlap (HCV-AIH), and who achieved virologic cure using direct-acting antiviral agents (DAA). METHODS Characteristics of HCV-AIH patients who underwent paired liver biopsies before and after receiving DAA treatment from 2011 to 2018 were evaluated. RESULTS Five HCV-AIH patients (three male; mean age, 60.4 years) underwent paired liver biopsies (average interval, 2.3 years) before and after achieving cure with DAA treatment. All patients showed virologic response, while four showed decreased inflammation, and three cases showed features of fibrosis regression. Immunohistochemical staining demonstrated significant decrease in plasma cell count in three patients (20.6 vs 11.9 plasma cells/high power field; P = .02, t test). CONCLUSIONS Histologic improvements in inflammation and fibrosis are noted in most HCV-AIH patients after DAA treatment, suggesting that the autoimmune component of the HCV-AIH overlap syndrome is merely a secondary phenomenon of viral infection.
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Affiliation(s)
- Juan Putra
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
- Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada
| | - Thomas D Schiano
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
- Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - M Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
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16
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Simoes CC, Saldarriaga OA, Utay NS, Stueck AE, Merwat SK, Merwat SN, Schiano TD, Fiel MI, Stevenson HL. Direct-Acting Antiviral Treatment of Patients with Hepatitis C Resolves Serologic and Histopathologic Features of Autoimmune Hepatitis. Hepatol Commun 2019; 3:1113-1123. [PMID: 31388631 PMCID: PMC6671831 DOI: 10.1002/hep4.1388] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 05/17/2019] [Indexed: 12/15/2022] Open
Abstract
Patients with hepatitis C virus (HCV) often have elevated serum markers and histologic features of autoimmune hepatitis (AIH). We evaluated an HCV-positive (HCV+) study group that had elevated serum markers of AIH before starting direct-acting antiviral (DAA) therapy (n = 21) and compared them to an HCV+ control group that did not have laboratory studies suggesting AIH (n = 21). Several patients in the study (17/21) and control (11/21) groups had liver biopsies before DAA treatment, and many were biopsied due to elevated serum markers of AIH. Evaluation of pre-DAA treatment liver biopsies showed histologic features suggestive of AIH in 64.7% (11/17) of the study group and 45.5% (5/11) of the control group. Patients who were HCV+ with elevated serum markers of AIH had significantly increased hepatitis activity (P < 0.001) and slightly increased fibrosis stages (P = 0.039) in their pretreatment liver biopsies compared to controls. We hypothesized that the elevated serum markers and histologic features of AIH would resolve following DAA treatment. Serum markers of AIH in the study group began decreasing by 6 months posttreatment, and 52.4% (11/21) had complete resolution. Alanine aminotransferase levels significantly decreased into the normal range for all patients (21/21). Even patients that had persistence of serum markers of AIH after DAA treatment had normal transaminases. Six patients from the study patient group and 4 patients from the control group had follow-up liver biopsies after DAA treatment, and all biopsies showed resolution of the histologic features of AIH. Conclusion: The majority of HCV+ patients that have serum markers and/or histopathologic features of AIH should initially be treated with DAA.
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Affiliation(s)
- Camila C Simoes
- Department of Pathology University of Texas Medical Branch Galveston TX
| | | | - Netanya S Utay
- Infectious Disease Division, Department of Internal Medicine University of Texas Health Science Center at Houston Houston TX
| | | | - Sheharyar K Merwat
- Department of Gastroenterology and Hepatology University of Texas Medical Branch Galveston TX
| | - Shehzad N Merwat
- Department of Gastroenterology and Hepatology University of Texas Medical Branch Galveston TX
| | - Thomas D Schiano
- Department of Hepatology Icahn School of Medicine at Mount Sinai New York NY
| | - Maria Isabel Fiel
- Department of Pathology Icahn School of Medicine at Mount Sinai New York NY
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