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Bader El Din NG, Farouk S. Exploring the Impact of Different Inflammatory Cytokines on Hepatitis C Virus Infection. J Interferon Cytokine Res 2024; 44:233-243. [PMID: 38563804 DOI: 10.1089/jir.2024.0003] [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: 04/04/2024] Open
Abstract
Hepatitis C virus (HCV) infection is a global health concern affecting millions worldwide. Chronic HCV infection often leads to liver inflammation and can progress to cirrhosis and hepatocellular carcinoma. Inflammatory cytokines are crucial in modulating the immune response during HCV infection. This review aims to investigate the impact of different inflammatory cytokines on HCV infection and associated immune responses. This review was conducted to identify relevant studies on the interplay between inflammatory cytokines and HCV infection. The analysis focused on the effects of key inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-gamma (IFN-γ), on HCV replication, immune cell activation, and liver inflammation. The findings reveal that these inflammatory cytokines can significantly influence HCV infection and the subsequent immune response. TNF-α, IL-6, and IL-1 have been shown to enhance HCV replication, while IFN-γ exerts antiviral effects by inhibiting viral replication and promoting immune cell-mediated clearance of infected hepatocytes. Moreover, these cytokines contribute to the recruitment and activation of immune cells, such as natural killer cells, T cells, and macrophages, which play critical roles in controlling HCV infection. Understanding the precise mechanisms by which inflammatory cytokines impact HCV infection is crucial for developing more targeted therapeutic strategies. Modulating the levels or activity of specific cytokines may provide opportunities to attenuate HCV replication, reduce liver inflammation, and improve treatment outcomes. In conclusion, this review highlights the significance of inflammatory cytokines in influencing HCV infection and associated immune responses.
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Affiliation(s)
- Noha G Bader El Din
- Microbial Biotechnology Department, Biotechnology Institute, National Research Center, Cairo, Egypt
| | - Sally Farouk
- Microbial Biotechnology Department, Biotechnology Institute, National Research Center, Cairo, Egypt
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Shive CL, Kowal CM, Desotelle AF, Nguyen Y, Carbone S, Kostadinova L, Davitkov P, O’Mara M, Reihs A, Siddiqui H, Wilson BM, Anthony DD. Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection. Cells 2023; 12:2034. [PMID: 37626844 PMCID: PMC10453378 DOI: 10.3390/cells12162034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/29/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy. IL-6, IP10, Endocab, LBP, and FABP were elevated in HCV participants, as were T cell co-expression of exhaustion and senescence markers. We found positive associations between IL-6, IP10, EndoCab, LBP, and co-expression of T cell markers of exhaustion and senescence. We also found numerous associations between reduced liver function, as measured by plasma albumin levels, and T cell exhaustion/senescence, inflammation, and endotoxemia. We found positive associations between liver stiffness (TE score) and plasma levels of IL-6, IP10, and LBP. Lastly, plasma IP10 and the proportion of CD8 T cells co-expressing PD-1 and CD57 decreased after initiation of direct-acting anti-viral therapy. Although associations do not prove causality, our results support the model that translocation of microbial products, resulting from decreased liver blood filtration, during HCV infection drives chronic inflammation that results in T cell exhaustion/senescence and contributes to systemic immune dysfunction.
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Affiliation(s)
- Carey L. Shive
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
- Pathology Department, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Corinne M. Kowal
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Alexandra F. Desotelle
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Ynez Nguyen
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Sarah Carbone
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Lenche Kostadinova
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Perica Davitkov
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Megan O’Mara
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Alexandra Reihs
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Hinnah Siddiqui
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Brigid M. Wilson
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Donald D. Anthony
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Wang Y, Hu Y, Zhang X, Luo Y, Ma L, Lu J, Liang Q, Xu C, Zhao C, Pan CQ. IP-10 Interferes With the Antiviral Response of Direct-Acting Antiviral Agents for Hepatitis C Virus Infection. Front Public Health 2022; 10:911551. [PMID: 35923969 PMCID: PMC9342904 DOI: 10.3389/fpubh.2022.911551] [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: 04/02/2022] [Accepted: 06/20/2022] [Indexed: 12/02/2022] Open
Abstract
Background Increased interferon (IFN)-gamma inducible protein-10 (IP-10) level has been shown to be associated with sustained virologic responses (SVRs) to pegylated interferon-alpha 2a/ribavirin-based therapy in patients with chronic hepatitis C (CHC). We investigated the relationship between IP-10 and treatment response in patients with CHC treated with direct-acting antiviral agents (DAAs) therapy. Methods We measured the dynamic changes of IP-10 in samples from 90 patients with CHC. The serum IP-10 levels, intrahepatic expressions of IP-10 mRNA, and protein were determined, respectively. For the in vitro experiments, the expression changes of IP-10 in hepatitis C virus (HCV)-replicating Huh-7 cells with or without non-structural protein 5A (NS5A) inhibitor were analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting. Results Patients with chronic hepatitis C had increased baseline IP-10 levels, intrahepatic IP-10 mRNA, and protein expression. After initiating DAAs therapy, serum IP-10 levels decreased gradually in patients who achieved cure, whereas in patients who failed the therapy, IP-10 levels did not change significantly or recovered from the initial decline. Multivariate logistic regression analysis confirmed that baseline IP-10 level ≤ 450 pg/ml and decline >30% at 12 weeks independently predicted the SVR in patients with CHC who received DAAs. In vitro, the expression of IP-10 mRNA and protein in HCV-replicating Huh-7 cells increased significantly. However, such activities were downregulated by NS5A inhibitor, followed by the reduction of HCV RNA levels and a decline in IP-10 levels. Conclusion IP-10 interfered with HCV replication in hepatocytes and the dynamic decline in IP-10 levels during DAA treatment predicted the SVR in patients with CHC.
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Affiliation(s)
- Yadong Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yangyang Hu
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xing Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yue Luo
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Luyuan Ma
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jingjing Lu
- Department of Infectious Diseases, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Qianfei Liang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chengjun Xu
- Department of Infectious Diseases, People's Hospital of Kuancheng Manchu Nationality Autonomous County, Chengde, China
| | - Caiyan Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Caiyan Zhao
| | - Calvin Q. Pan
- Center for Liver Diseases, Beijing Ditan Hospital, Capital Medical Univerisity, Beijing, China
- Division of Gastroenterology and Hepatology, NYU Langone Health, New York University School of Medicine, New York, NY, United States
- Calvin Q. Pan
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Ibrahim HM, Abdel-Ghaffar FR, Zied AB, El-Ghareeb SH. Assessment of the Sofosbuvir + Daclatasvir (±) Ribavirin Treatment and the Prognostic Efficacy of Interferon-gamma Induced Protein 10, Macrophage Inflammatory-1-Beta, and C-reactive Protein in Hepatitis C Egyptian Patients' Therapy Outcome. BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL (BBRJ) 2022; 6:109-116. [DOI: 10.4103/bbrj.bbrj_209_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Background:
Hepatitis C virus (HCV) is the most important virus among the infectious agents as the cause of liver disease in Egypt. The aim of this work was to assess the efficacy and tolerability of the sofosbuvir + daclatasvir (±) ribavirin (SOF + DCV [±] RBV) regimens and to evaluate the association of interferon-gamma induced protein 10 (IP-10) and macrophage inflammatory-1-beta (MIP-1β) and C-reactive protein (CRP) with treatment responses as potential biomarkers for the prognosis of HCV in patients from Kafer EL-Sheikh Province, Egypt.
Methods:
HCV Patients were treated with a combined treatment of SOF plus DCV with or without RBV for 12 weeks. The biochemical, hematological parameters, HCV RNA load, IP-10, MIP-1β, and CRP were detected pre- and post-treatment.
Results:
Both SOF-based regimens improved the liver function, anemia, leukopenia, and thrombocytopenia especially after treatment with SOF, DCV, and RBV. Sustained virological response 12 was slightly higher in the group receiving (SOF and DCV) therapy (99.42%) when compared to (SOF, DCV, and RBV) therapy (98.44%). The most common adverse events were fatigue, headache, anorexia, rash, and nausea. Interestingly, higher levels of the IP-10, MIP-1β, or CRP were observed in the serum of patients with HCV before treatment, and their levels significantly decreased after the treatment of both regimens.
Conclusions:
Our study revealed that SOF-based regimens are efficacious in controlling the HCV load and IP-10, MIP-1β, or CRP have both bioprognostic efficacy and potential role in predicting treatment responses.
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Changes in serum interferon-γ-inducible protein-10 levels and liver stiffness among chronic hepatitis C Egyptian patients in response to directly acting antiviral agents. Eur J Gastroenterol Hepatol 2021; 33:e335-e340. [PMID: 33470694 DOI: 10.1097/meg.0000000000002059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Interferon-γ inducible protein-10 (IP-10) is chemokine biomarker of liver inflammation, elevated in patients with chronic hepatitis C infection. AIMS Investigating if changes in serum IP-10 levels in response to directly acting antiviral agents (DAAs) treatment for chronic HCV patients are paralleled by changes in liver stiffness measurements (LSM), and assessing role of using serum IP-10 as a noninvasive accurate method to predict changes in hepatic necro-inflammation and fibrosis. MATERIAL AND METHODS A prospective observational study included 92 Egyptian chronic HCV patients, who received treatment with sofosbuvir with daclatasvir regimen. Patients were classified into two groups; group I (53 patients) with non to mild significant liver fibrosis (F0-F1), and group II (39 patients) with significant to advanced liver fibrosis (F2-F4). Fibroscan and serum IP-10 were assessed pretreatment and 3 months after end of treatment. RESULTS All patients achieved SVR. Both IP-10 and LSM showed significant decline after treatment in both groups. No significant correlation was found between changes in LSM and IP-10. IP-10 detected liver cirrhosis at cut off level of 17.8 pg/ml, with 75% sensitivity and 73.86% specificity, with area under the curve = 0.66, however, IP-10 had no statistical significance in detecting advanced fibrosis. CONCLUSION IP-10 might be of significance as a noninvasive predictor of liver cirrhosis. IP-10 significant decline post-DAAs treatment in chronic HCV genotype IV infected patients reflects significant improvement in fibrosis stage and hepatic necro-inflammation in response to treatment. No significant correlation was detected in the changes of both IP-10 and LSM.
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Altobje MA, Al-Rrassam ZT. The Estimate of Interferon-inducible Protein-10 and Interferon-γ in Hemodialysis Patients with Chronic HCV. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Due to the rise in the number of deaths, the hepatitis C virus remains a public health issue worldwide. During the recovery period, cytokines are known as indicators of chronic liver infection.
AIM: In this study, immunological parameters were measured and calculated in chronic hemodialysis patients after more than 6 months of drug administration.
METHODS: We have picked 60 patients with hemodialysis who are anti-HCV positive. ELISA and the calculation of alkaline phosphatase (ALP) were used to evaluate IP-10 and IFN-γ.
RESULTS: A substantial association between variables and infected cases was found. No worth was considered for genders or age categories.
CONCLUSIONS: The serum IP-10 level can be a warning primarily for patients who have taken a variety of prescriptions intermittently. In both the RPT and RST cohorts, IFN-γ serum levels are usually elevated. Serum level ALP is not a particular chronic HCV predictor.
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Ho CM, Chen CL, Chang CH, Lee MR, Wang JY, Hu RH, Lee PH. Circulatory Inflammatory Mediators in the Prediction of Anti-Tuberculous Drug-Induced Liver Injury Using RUCAM for Causality Assessment. Biomedicines 2021; 9:891. [PMID: 34440095 PMCID: PMC8389605 DOI: 10.3390/biomedicines9080891] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Anti-tuberculous (TB) medications are common causes of drug-induced liver injury (DILI). Limited data are available on systemic inflammatory mediators as biomarkers for predicting DILI before treatment. We aimed to select predictive markers among potential candidates and to formulate a predictive model of DILI for TB patients. METHODS Adult active TB patients from a prospective cohort were enrolled, and all participants received standard anti-tuberculous treatment. Development of DILI, defined as ≥5× ULN for alanine transaminase or ≥2.6× ULN of total bilirubin with causality assessment (RUCAM, Roussel Uclaf causality assessment method), was regularly monitored. Pre-treatment plasma was assayed for 15 candidates, and a set of risk prediction scores was established using Cox regression and receiver-operating characteristic analyses. RESULTS A total of 19 (7.9%) in 240 patients developed DILI (including six carriers of hepatitis B virus) following anti-TB treatment. Interleukin (IL)-22 binding protein (BP), interferon gamma-induced protein 1 (IP-10), soluble CD163 (sCD163), IL-6, and CD206 were significant univariable factors associated with DILI development, and the former three were backward selected as multivariable factors, with adjusted hazards of 0.20 (0.07-0.58), 3.71 (1.35-10.21), and 3.28 (1.07-10.06), respectively. A score set composed of IL-22BP, IP-10, and sCD163 had an improved area under the curve of 0.744 (p < 0.001). CONCLUSIONS Pre-treatment IL-22BP was a protective biomarker against DILI development under anti-TB treatment, and a score set by additional risk factors of IP-10 and sCD163 employed an adequate DILI prediction.
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Affiliation(s)
- Cheng-Maw Ho
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan; (C.-M.H.); (R.-H.H.); (P.-H.L.)
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 10617, Taiwan;
| | - Chia-Hao Chang
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; (C.-H.C.); (M.-R.L.)
| | - Meng-Rui Lee
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; (C.-H.C.); (M.-R.L.)
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan
| | - Jann-Yuan Wang
- Department of Internal Medicine, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; (C.-H.C.); (M.-R.L.)
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan
| | - Rey-Heng Hu
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan; (C.-M.H.); (R.-H.H.); (P.-H.L.)
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei 10617, Taiwan; (C.-M.H.); (R.-H.H.); (P.-H.L.)
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Asadzadeh R, Ahmadpoor P, Nafar M, Samavat S, Nikoueinejad H, Hosseinzadeh M, Mamizadeh N, Hatami S, Masoumi E, Amirzargar A. Association of IL-15 and IP-10 Serum Levels with Cytomegalovirus Infection, CMV Viral Load and Cyclosporine Level after Kidney Transplantation. Rep Biochem Mol Biol 2021; 10:216-223. [PMID: 34604411 PMCID: PMC8480297 DOI: 10.52547/rbmb.10.2.216] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/08/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is the most common complications following kidney transplantation. Natural killer (NK) cells demonstrated critical anti-viral role in controlling and elimination of CMV after transplantation. Interleukin-15 (IL-15) is a pleiotropic cytokine that promotes the activity of NK cells and strengthens the acquired immune system. Also, IP10 (CXCL10) is a chemotactic factor which regulates NK cell recruitment and antiviral immune response. We aimed to determine the correlation between the serum levels of IL-15 and IP-10 cytokines with CMV infection, CMV viral load, and cyclosporine as a major immunosuppressive treatment after transplantation. METHODS Fifty-eight kidney transplant recipient patients without evidence of CMV virus disease before transplantation surgery were included in the study. From the day of transplant surgery, the patients were evaluated based on the presence of CMV Ag pp65, CMV viral load, serum levels of IL-15 & IP-10, Cyclosporine levels (C0 & C2), Glomerular Filtration Rate (GFR), and hematological & biochemical Index, up to 75 days. RESULTS Comparison analysis of serum levels of IL-15 and IP-10 showed no significant association with CMV infection in kidney transplant recipients. In addition, CMV viral load and cyclosporine levels at C0 and C2 did not affect patients' IL-15 and IP-10 levels. CONCLUSION The levels of IP-10 and IL-15 cytokines are not affected with CMV infection, even if a viral infection occurs in the early days after transplantation or long afterwards. In addition, taking the different levels of cyclosporine did not affect the cytokines levels. Other mechanisms may play a role in maintaining the levels of these cytokines.
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Affiliation(s)
- Reza Asadzadeh
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Pedram Ahmadpoor
- Urology and Nephrology Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohsen Nafar
- Urology and Nephrology Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Shima Samavat
- Urology and Nephrology Research Center, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Hassan Nikoueinejad
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Morteza Hosseinzadeh
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.
| | - Nahid Mamizadeh
- Department of Nephrology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.
| | - Saeideh Hatami
- Department of Tissue Engineering and Regenerative Medicine, Iran university of Medical Sciences, Tehran, Iran.
| | - Elham Masoumi
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Parlati L, Hollande C, Pol S. Treatment of hepatitis C virus infection. Clin Res Hepatol Gastroenterol 2021; 45:101578. [PMID: 33272891 DOI: 10.1016/j.clinre.2020.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus infection affects 71 million people worldwide. It is at the origin of a multi-organ disease associating hepatic manifestations, cryoglobulinemic vasculitis and general manifestations linked to chronic inflammation (diabetes, cardio-, reno- or cerebrovascular manifestations, extra-hepatic cancers including non-Hodgkin's lymphoma). The significant morbidity and mortality linked to the hepatitis C virus therefore justify its screening and access to treatments which have increased considerably over the past two decades. Understanding the replicative cycle of the hepatitis C virus has enabled the development of direct HCV-specific antivirals targeting viral proteins (NS3/4A protease, NS5B polymerase and the multifunctional NS5A replication complex). The combination of two to three specific inhibitors often co-formulated in a capsule, without pegylated interferon and most often without ribavirin, allows high antiviral efficacy (more than 97% cure) for a treatment duration of 8-12 weeks with satisfactory tolerance. HCV infection is the only chronic viral infection that can be cured and the hepatic or extrahepatic manifestations are mainly reversible. This underlines the importance of strengthening screening and access to care policies in order to achieve the elimination of viral infection C in the short term, in 2030, as expected from the program of the World Health Organization. If this elimination is possible in some countries (Iceland, France, Germany …), it seems compromised in others where prevention (USA), screening and/or access to care are still insufficient (Sub-Saharan Africa, Russia…).
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Affiliation(s)
- Lucia Parlati
- Département d'Hépatologie, APHP, Hôpital Cochin, Paris, France
| | - Clémence Hollande
- Département d'Hépatologie, APHP, Hôpital Cochin, Paris, France; Université de Paris, Inserm U-1223 et Immunité des Cellules Dendritiques, Institut Pasteur, Paris, France
| | - Stanislas Pol
- Département d'Hépatologie, APHP, Hôpital Cochin, Paris, France; Université de Paris, Inserm U-1223 et Immunité des Cellules Dendritiques, Institut Pasteur, Paris, France.
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Aregay A, Engel B, Port K, Vondran FWR, Bremer B, Niehaus C, Khera T, Richter N, Jaeckel E, Cornberg M, Taubert R, Wedemeyer H. Distinct Immune Imprints of Post-Liver Transplantation Hepatitis C Persist Despite Viral Clearance. Liver Transpl 2021; 27:887-899. [PMID: 33641215 DOI: 10.1002/lt.26031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 01/13/2023]
Abstract
Recurrence or de novo infection of hepatitis C virus (HCV) after liver transplantation (LT) has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of HCV LT is unknown. We studied 74 protein biomarkers in the plasma of LT patients receiving antiviral therapy. In addition, deep immune phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed. We found that LT patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL)-18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-beta, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants. Interestingly, patients who cleared HCV after LT did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence. Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets after LT are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV after LT did not trigger rejection episodes in many patients.
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Affiliation(s)
- Amare Aregay
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Christian Niehaus
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Tanvi Khera
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Nicolas Richter
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research, DZIF, partner-site Hannover-Braunschweig, Hannover, Germany.,Centre for individualized infection medicine (CIIM), Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research, DZIF, partner-site Hannover-Braunschweig, Hannover, Germany
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11
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Cytokine expression patterns in hospitalized children with Bordetella pertussis, Rhinovirus or co-infection. Sci Rep 2021; 11:10948. [PMID: 34040002 PMCID: PMC8154898 DOI: 10.1038/s41598-021-89538-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/12/2021] [Indexed: 02/02/2023] Open
Abstract
Mechanisms of interaction between Bordetella pertussis and other viral agents are yet to be fully explored. We studied the inflammatory cytokine expression patterns among children with both viral-bacterial infections. Nasopharyngeal aspirate (NPA) samples were taken from children, aged < 1 year, positive for Rhinovirus, Bordetella pertussis and for Rhinovirus and Bordetella pertussis. Forty cytokines were evaluated in NPA by using human cytokine protein arrays and a quantitative analysis was performed on significantly altered cytokines. Forty cytokines were evaluated in NPA by using human cytokine protein arrays and a quantitative analysis was performed on significantly altered cytokines. Our results show that co-infections display a different inflammatory pattern compared to single infections, suggesting that a chronic inflammation caused by one of the two pathogens could be the trigger for exacerbation in co-infections.
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12
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Wang CC, Tseng KC, Tzeng IS, Kao JH. The impact of cytokine change after hepatitis C virus clearance by direct antiviral agents on the risk of hepatocellular carcinoma. J Formos Med Assoc 2021; 120:965-973. [PMID: 33129621 DOI: 10.1016/j.jfma.2020.10.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/30/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE De novo and early recurrent hepatocellular carcinoma (HCC) have been observed in clinical practice after direct antiviral agents (DAA) treatment. The study aims to investigate the change of cytokines and growth factors after hepatitis C virus (HCV) clearance by DAAs and their impact on the risk of HCC development. METHODS The chronic hepatitis C (CHC) patients with or without HCC who received DAA treatment were prospectively enrolled. The cytokines and growth factors were measured using Bio-Plex Pro™ Human Cytokine 27-plex Assay before and 12 weeks off DAA treatment. RESULTS A total of 37 patients were enrolled for final analysis. There were 11 males (29.7%) and 26 females (70.3%). The mean age was 67.39 ± 10.48 years. 11 (29.7%) patients were HCV-related HCC patients. The HCV genotype included genotype 2 in 26 patients and genotype 1b in 10 patients, and genotype 6 in 1. Among them, 35 (94.6%) patients achieved sustained virologic response (SVR). Two patients with HCC failed to DAA treatment. In HCV-related HCC patients, serum IP-10 level significantly declined after HCV clearance, but no difference in five growth factors including G-CSF, GM-CSF, basic FGF, PDGF-BB, and VEGF. Several cytokines including IP-10 significantly declined after HCV clearance in CHC patients. CONCLUSION This study showed only serum IP-10 level, a risk factor of HCC, was significantly declined after HCV clearance and no change in the markers of growth factors in HCV-related HCC patients, suggesting no promotion of HCC using DAA treatment for HCV-related HCC patients.
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Affiliation(s)
- Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Kuo-Chih Tseng
- Department of Gastroenterology, Da-Lin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - I-Shiang Tzeng
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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13
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Cheng X, Uchida T, Xia Y, Umarova R, Liu CJ, Chen PJ, Gaggar A, Suri V, Mücke MM, Vermehren J, Zeuzem S, Teraoka Y, Osawa M, Aikata H, Tsuji K, Mori N, Hige S, Karino Y, Imamura M, Chayama K, Liang TJ. Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection. J Clin Invest 2021; 130:3205-3220. [PMID: 32163375 DOI: 10.1172/jci135616] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/05/2020] [Indexed: 12/12/2022] Open
Abstract
In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.
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Affiliation(s)
- Xiaoming Cheng
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Takuro Uchida
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuchen Xia
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Regina Umarova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Anuj Gaggar
- Gilead Sciences, Foster City, California, USA
| | | | - Marcus M Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Johannes Vermehren
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Shuhei Hige
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yoshiyasu Karino
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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14
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Xiao L, Wu X, Zhang F, Wang J, Xu X, Li L. Changes of inflammatory cytokines/chemokines during ravidasvir plus ritonavir-boosted danoprevir and ribavirin therapy for patients with genotype 1b hepatitis C infection. J Med Virol 2020; 92:3516-3524. [PMID: 32525562 DOI: 10.1002/jmv.26161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/05/2020] [Accepted: 06/07/2020] [Indexed: 01/02/2023]
Abstract
This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment-naïve non-cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV-host interactions during anti-HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12-weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12-weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy-five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment-related serious AEs or AEs leading to discontinuation were reported. The serum HCV-RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon-inducible protein-10 (IP-10) decreased after anti-HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP-10 has the potential to be an indicator of innate immune viral recognition.
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Affiliation(s)
- Lanlan Xiao
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxin Wu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fen Zhang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Wang
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaowei Xu
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- Infections Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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15
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Chen H, Humes ST, Rose M, Robinson SE, Loeb JC, Sabaraya IV, Smith LC, Saleh NB, Castleman WL, Lednicky JA, Sabo-Attwood T. Hydroxyl functionalized multi-walled carbon nanotubes modulate immune responses without increasing 2009 pandemic influenza A/H1N1 virus titers in infected mice. Toxicol Appl Pharmacol 2020; 404:115167. [PMID: 32771490 PMCID: PMC10636740 DOI: 10.1016/j.taap.2020.115167] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 07/20/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022]
Abstract
Growing use of carbon nanotubes (CNTs) have garnered concerns regarding their association with adverse health effects. Few studies have probed how CNTs affect a host's susceptibility to pathogens, particularly respiratory viruses. We reported that exposure of lung cells and mice to pristine single-walled CNTs (SWCNTs) leads to significantly increased influenza virus H1N1 strain A/Mexico/4108/2009 (IAV) titers in concert with repressed antiviral immune responses. In the present study, we investigated if hydroxylated multi-walled CNTs (MWCNTs), would result in similar outcomes. C57BL/6 mice were exposed to 20 μg MWCNTs on day 0 and IAV on day 3 and samples were collected on day 7. We investigated pathological changes, viral titers, immune-related gene expression in lung tissue, and quantified differential cell counts and cytokine and chemokine levels in bronchoalveolar lavage fluid. MWCNTs alone caused mild inflammation with no apparent changes in immune markers whereas IAV alone presented typical infection-associated inflammation, pathology, and titers. The co-exposure (MWCNTs + IAV) did not alter titers or immune cell profiles compared to the IAV only but increased concentrations of IL-1β, TNFα, GM-CSF, KC, MIPs, and RANTES and inhibited mRNA expression of Tlr3, Rig-i, Mda5, and Ifit2. Our findings suggest MWCNTs modulate immune responses to IAV with no effect on the viral titer and modest pulmonary injury, a result different from those reported for SWCNT exposures. This is the first study to show that MWCNTs modify cytokine and chemokine responses that control aspects of host defenses which may play a greater role in mitigating IAV infections.
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Affiliation(s)
- Hao Chen
- Department of Environmental and Global Health, Center for Environmental and Human Toxicology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Sara T Humes
- Department of Environmental and Global Health, Center for Environmental and Human Toxicology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Melanie Rose
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Sarah E Robinson
- Department of Environmental and Global Health, Center for Environmental and Human Toxicology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Julia C Loeb
- Department of Environmental and Global Health, Center for Environmental and Human Toxicology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Indu V Sabaraya
- Department of Civil, Architectural, and Environmental Engineering, University of Texas Austin, Austin, TX, 78712, USA
| | - L Cody Smith
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Navid B Saleh
- Department of Civil, Architectural, and Environmental Engineering, University of Texas Austin, Austin, TX, 78712, USA
| | - William L Castleman
- Department of Infectious Diseases and Pathology, College of Veterinary Medicine, Gainesville, FL 32611, USA
| | - John A Lednicky
- Department of Environmental and Global Health, Center for Environmental and Human Toxicology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
| | - Tara Sabo-Attwood
- Department of Environmental and Global Health, Center for Environmental and Human Toxicology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA.
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16
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Álvarez B, Restrepo C, García M, Navarrete-Muñoz MA, Jiménez-Sousa MA, Prieto L, Cabello A, Nistal S, Resino S, Górgolas M, Rallón N, Benito JM. Liver Stiffness Hinders Normalization of Systemic Inflammation and Endothelial Activation after Hepatitis C Virus (HCV) Eradication in HIV/HCV Coinfected Patients. Vaccines (Basel) 2020; 8:vaccines8020323. [PMID: 32575428 PMCID: PMC7350227 DOI: 10.3390/vaccines8020323] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/12/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
Systemic inflammation, endothelial dysfunction and coagulopathy are of high clinical relevance in the management of people living with HIV (PLWH), and even more in patients coinfected with hepatitis C virus (HCV). It has been suggested a significant impact of HCV coinfection on these conditions. However, HCV can be eradicated in most patients with the new direct-acting antivirals (DAAs) therapy. We have analyzed the effect of HCV on systemic inflammation, endothelial activation and coagulopathy in PLWH and its evolution after HCV eradication with DAAs. Twenty-five HIV/HCV coinfected (HIV/HCV group), 25 HIV monoinfected (HIV group) and 20 healthy controls (HC) were included in the study. All patients were on ART and HIV suppressed. Levels of fourteen markers of systemic inflammation, endothelial activation and coagulopathy (IL-1ß, IL-6, IL-12p70, IL-8, TNFα, D-dimer, Eotaxin, IL-18, IP-10, monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), TNFα receptor 1 (TNFR1), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1)) were measured on plasma at baseline and after DAAs-mediated HCV eradication. Non-parametric tests were used to establish inter/intra-group differences. At baseline, the HIV/HCV group showed increased levels of IL-18 (p = 0.028), IP-10 (p < 0.0001), VCAM-1 (p < 0.0001) and ICAM-1 (p = 0.045), compared to the HC and HIV groups, with the highest levels for IL18 and IP10 observed in HIV/HCV patients with increased liver stiffness (≥7.1 KPa). Eradication of HCV with DAAs-based therapy restored some but not all the evaluated parameters. VCAM-1 remained significantly increased compared to HC (p = 0.001), regardless of the level of basal liver stiffness in the HIV/HCV group, and IP-10 remained significantly increased only in the HIV/HCV group, with increased level of basal liver stiffness compared to the HC and to the HIV groups (p = 0.006 and p = 0.049, respectively). These data indicate that DAAs therapy in HIV/HCV co-infected patients and HCV eradication does not always lead to the normalization of systemic inflammation and endothelial dysfunction conditions, especially in cases with increased liver stiffness.
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Affiliation(s)
- Beatriz Álvarez
- Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain; (B.Á.); (L.P.); (A.C.); (M.G.)
| | - Clara Restrepo
- HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain; (C.R.); (M.G.); (M.A.N.-M.)
- Hospital Universitario Rey Juan Carlos, 28933 Móstoles, Spain;
| | - Marcial García
- HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain; (C.R.); (M.G.); (M.A.N.-M.)
- Hospital Universitario Rey Juan Carlos, 28933 Móstoles, Spain;
| | - María A. Navarrete-Muñoz
- HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain; (C.R.); (M.G.); (M.A.N.-M.)
- Hospital Universitario Rey Juan Carlos, 28933 Móstoles, Spain;
| | - María A. Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28040 Madrid, Spain; (M.A.J.-S.); (S.R.)
| | - Laura Prieto
- Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain; (B.Á.); (L.P.); (A.C.); (M.G.)
| | - Alfonso Cabello
- Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain; (B.Á.); (L.P.); (A.C.); (M.G.)
| | - Sara Nistal
- Hospital Universitario Rey Juan Carlos, 28933 Móstoles, Spain;
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28040 Madrid, Spain; (M.A.J.-S.); (S.R.)
| | - Miguel Górgolas
- Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain; (B.Á.); (L.P.); (A.C.); (M.G.)
| | - Norma Rallón
- HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain; (C.R.); (M.G.); (M.A.N.-M.)
- Hospital Universitario Rey Juan Carlos, 28933 Móstoles, Spain;
- Correspondence: or (N.R.); or (J.M.B.)
| | - José M. Benito
- HIV and Viral Hepatitis Research Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain; (C.R.); (M.G.); (M.A.N.-M.)
- Hospital Universitario Rey Juan Carlos, 28933 Móstoles, Spain;
- Correspondence: or (N.R.); or (J.M.B.)
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17
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Impact of IFN-Free and IFN-Based Treatment on Blood Myeloid Dendritic Cell, Monocyte, Slan-DC, and Activated T Lymphocyte Dynamics during HCV Infection. J Immunol Res 2020; 2020:2781350. [PMID: 32258171 PMCID: PMC7102477 DOI: 10.1155/2020/2781350] [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: 05/23/2019] [Revised: 12/20/2019] [Accepted: 02/24/2020] [Indexed: 11/18/2022] Open
Abstract
Chronic hepatitis C virus infection leads to the activation of innate immunity, a key component in HCV fibrosis. In the past, the use of IFN-based treatment regimens did not permit an adequate evaluation of the impact of HCV clearance on immune cells, because of their antiviral and immunomodulatory properties. The recent development of direct-acting antiviral (DAA) therapy, which is associated with high rates of sustained virological response, enables a more accurate analysis of the immunological modifications following HCV eradication. We studied the dynamics of blood myeloid dendritic cells, monocytes, slan-DCs, and T lymphocytes during IFN-free and IFN-based regimens in hepatitis C virus infection.
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18
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Ferrari SM, Fallahi P, Ruffilli I, Elia G, Ragusa F, Paparo SR, Patrizio A, Mazzi V, Colaci M, Giuggioli D, Ferri C, Antonelli A. Immunomodulation of CXCL10 Secretion by Hepatitis C Virus: Could CXCL10 Be a Prognostic Marker of Chronic Hepatitis C? J Immunol Res 2019; 2019:5878960. [PMID: 31485460 PMCID: PMC6702819 DOI: 10.1155/2019/5878960] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/19/2019] [Accepted: 04/30/2019] [Indexed: 12/17/2022] Open
Abstract
Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and "chronic hepatitis C virus (HCV) infection" (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.
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Affiliation(s)
| | - Poupak Fallahi
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Ilaria Ruffilli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giusy Elia
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesca Ragusa
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Armando Patrizio
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Valeria Mazzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Michele Colaci
- Internal Medicine Unit, Cannizzaro Hospital, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Dilia Giuggioli
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Clodoveo Ferri
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Pol S, Lagaye S. The remarkable history of the hepatitis C virus. Microbes Infect 2019; 21:263-270. [PMID: 31295571 DOI: 10.1016/j.micinf.2019.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/25/2019] [Accepted: 04/01/2019] [Indexed: 12/23/2022]
Abstract
The infection with the hepatitis C virus (HCV) is an example of the translational research success. The reciprocal interactions between clinicians and scientists have allowed in 30 years the initiation of empirical treatments by interferon, the discovery of the virus, the development of serological and virological tools for diagnosis but also for prognosis (the non-invasive biochemical or morphological fibrosis tests, the predictors of the specific immune response including genetic IL28B polymorphisms). Finally, well-tolerated and effective treatments with oral antivirals inhibiting HCV non-structural viral proteins involved in viral replication have been marketed this last decade, allowing the cure of all infected subjects. HCV chronic infection, which is a public health issue, is a hepatic disease which may lead to a cirrhosis and an hepatocellular carcinoma (HCC) but also a systemic disease with extra-hepatic manifestations either associated with a cryoglobulinemic vasculitis or chronic inflammation. The HCV infection is the only chronic viral infection which may be cured: the so-called sustained virologic response, defined by undetectable HCV RNA 12 weeks after the end of the treatment, significantly reduces the risk of morbidity and mortality associated with hepatic and extra-hepatic manifestations which are mainly reversible. The history of HCV ends with the pangenotypic efficacy of the multiple combinations, easy to use for 8-12 weeks with one to three pills per day and little problems of tolerance. This explains the short 30 years from the virus discovery to the viral hepatitis elimination policy proposed by the World Health Organization (WHO) in 2016.
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Affiliation(s)
- Stanislas Pol
- Université Paris Descartes, Paris, France; Département d'Hépatologie, Hôpital Cochin, APHP, Paris, France; INSERM UMS-20, Institut Pasteur, Paris, France; Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France; INSERM U1223, Institut Pasteur, Paris, France.
| | - Sylvie Lagaye
- Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France; INSERM U1223, Institut Pasteur, Paris, France.
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Pol S, Lagaye S. The remarkable history of the hepatitis C virus. Genes Immun 2019; 20:436-446. [PMID: 31019253 DOI: 10.1038/s41435-019-0066-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/25/2019] [Accepted: 04/01/2019] [Indexed: 02/06/2023]
Abstract
The infection with the hepatitis C virus (HCV) is an example of the translational research success. The reciprocal interactions between clinicians and scientists have allowed in 30 years the initiation of empirical treatments by interferon, the discovery of the virus, the development of serological and virological tools for diagnosis but also for prognosis (the non-invasive biochemical or morphological fibrosis tests, the predictors of the specific immune response including genetic IL28B polymorphisms). Finally, well-tolerated and effective treatments with oral antivirals inhibiting HCV non-structural viral proteins involved in viral replication have been marketed this last decade, allowing the cure of all infected subjects. HCV chronic infection, which is a public health issue, is a hepatic disease, which may lead to a cirrhosis and an hepatocellular carcinoma (HCC) but also a systemic disease with extra-hepatic manifestations either associated with a cryoglobulinemic vasculitis or chronic inflammation. The HCV infection is the only chronic viral infection, which may be cured: the so-called sustained virologic response, defined by undetectable HCV RNA 12 weeks after the end of the treatment, significantly reduces the risk of morbidity and mortality associated with hepatic and extra-hepatic manifestations, which are mainly reversible. The history of HCV ends with the pangenotypic efficacy of the multiple combinations, easy to use for 8-12 weeks with one to three pills per day and little problems of tolerance. This explains the short 30 years from the virus discovery to the viral hepatitis elimination policy proposed by the World Health Organization (WHO) in 2016.
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Affiliation(s)
- Stanislas Pol
- Université Paris Descartes, Paris, France. .,Département d'Hépatologie, Hôpital Cochin, APHP, Paris, France. .,INSERM UMS-20, Institut Pasteur, Paris, France. .,Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France. .,INSERM U1223, Institut Pasteur, Paris, France.
| | - Sylvie Lagaye
- Immunobiologie des Cellules Dendritiques, Institut Pasteur, Paris, France. .,INSERM U1223, Institut Pasteur, Paris, France.
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Rau M, Schmitt J, Berg T, Kremer AE, Stieger B, Spanaus K, Bengsch B, Romero MR, Marin JJ, Keitel V, Klinker H, Tony HP, Müllhaupt B, Geier A. Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients. PLoS One 2018; 13:e0208225. [PMID: 30507970 PMCID: PMC6277069 DOI: 10.1371/journal.pone.0208225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 11/14/2018] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND & AIMS Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients. METHODS In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS. RESULTS In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases. CONCLUSIONS A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.
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Affiliation(s)
- Monika Rau
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Johannes Schmitt
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Andreas E. Kremer
- Department of Medicine I, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Bruno Stieger
- Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
| | - Katharina Spanaus
- Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
| | - Bertram Bengsch
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Germany
- BIOSS Centre for Biological Signaling Studies, Freiburg, Germany
| | - Marta R. Romero
- Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, University of Salamanca, Salamanca, Spain
| | - Jose J. Marin
- Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, University of Salamanca, Salamanca, Spain
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany
| | - Hartwig Klinker
- Division of Infectious Disease, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Hans-Peter Tony
- Division of Rheumatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
- * E-mail:
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Xu XW, Wu XX, Chen KD, Chen DZ, Ou HL, Su JW, Yu HY, Yao HP, Li LJ. Patients with chronic hepatitis C receiving sofosbuvir and ribavirin-based treatment, with or without interferon in Zhejiang, China: An observational study. Medicine (Baltimore) 2018; 97:e12403. [PMID: 30235711 PMCID: PMC6160050 DOI: 10.1097/md.0000000000012403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 08/23/2018] [Indexed: 11/26/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the most important virus as the cause of liver disease in China. The aim of the present study was to explore whether sofosbuvir and ribavirin-based treatment can cure patients with chronic hepatitis C in eastern China. We examined a cohort of HCV-monoinfected patients and 9 patients agreed to participate in our treatment and research. The patients were diagnosed with chronic hepatitis C with or without cirrhosis. Nine patients including 4 female and 5 male met the requirements for selection and were willing to participate in this experiment. Sofosbuvir and ribavirin-based treatment with or without interferon was given to the patients. Viral loads, cytokines, and chemokines were recorded during treatment and after treatment. After 2 weeks of sofosbuvir and ribavirin-based treatment, the viral load of patients decreased to limits of detection. Eight patients were cured. Patients had rapid virological response (RVR) with undetectable viral load at week 4 and sustained virological response (SVR). The interferon-inducible protein-10 (IP-10) decreased after the treatment. However, the patient with cirrhosis failed, as the virus reappeared during SVR4. At the same time, the IP-10 dramatically increased as the relapse of the HCV virus. In summary, the IP-10 has the potential to be the biomarker for the prognostic of HCV.
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Determination of anti-HCV and quantification of HCV-RNA and IP-10 from dried blood spots sent by regular mail. PLoS One 2018; 13:e0201629. [PMID: 30063765 PMCID: PMC6067740 DOI: 10.1371/journal.pone.0201629] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/18/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND With the introduction of direct acting antivirals, treatment of hepatitis C virus (HCV) in hard-to-reach populations is now feasible. Therefore, new cost-effective and reliable test methods are needed. Determination of HCV antibodies and HCV-RNA from dried blood spots samples could represent one such method. Here we examined whether anti-HCV could be detected-and HCV-RNA quantified-from dried blood spots, sent by regular mail. We also investigated, if IP-10 determined from dried blood spots correlated with fibrosis progression appraised by transient elastography. METHOD Forty chronic HCV infected patients were consecutively enrolled. At baseline and after six months, dried blood spots were prepared from blood collected by venous puncture, dried for 4-6 hours, then stored in gas-impermeable plastic bags with a desiccator, before being sent by regular mail. At each visit, approximately six months apart, paired venous samples was obtained and analyzed for anti-HCV, HCV-RNA and IP-10. RESULTS Anti-HCV was found in 66/67 of the dried blood spots. Sixty-six paired samples were available for HCV-RNA analysis. A statistically significant correlation was found between log HCV-RNA concentrations in plasma, and log HCV-RNA obtained from (P < 0.0001, Pearson's R 0.6788, R2 0.4607). HCV-RNA, derived from DBS samples, was lower than the corresponding plasma concentration, reflected by a Bland-Altman bias of 3 with SD of bias ± 0.6472. We found no correlation between IP-10 and fibrosis progression. CONCLUSIONS We identified anti-HCV in 66/67samples, and quantified IP-10 and HCV-RNA from dried blood spots, dried at room temperature and sent by regular mail. HCV-RNA concentrations from the dried blood spots were lower than corresponding plasma values; a probable result of heparin coated test tubes. We found no correlation between IP-10 and fibrosis progression. Overall, dried blood spots could be a cost-effective and easy-to-use alternative to standard tests for the diagnosis of HCV infections.
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Venuto CS, Talal AH. Intrahepatic Sampling for the Elucidation of Antiviral Clinical Pharmacology. Clin Pharmacol Drug Dev 2018; 6:169-175. [PMID: 28263459 DOI: 10.1002/cpdd.311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 09/15/2016] [Indexed: 12/17/2022]
Abstract
Although the importance of the liver in clinical pharmacology is widely recognized, little is known in humans concerning its function in vivo at the hepatocyte level and how pharmacological functions are altered in the setting of advanced liver disease. Several recent proof-of-principle studies with first-generation DAAs have demonstrated the feasibility of serial liver sampling for pharmacological studies. These studies have begun to describe the liver-to-plasma concentration ratio and how this ratio is altered in the setting of advanced liver disease. These data are particularly relevant to individuals with substance-use disorders because many have advanced liver disease as a consequence of long-standing viral hepatitis infection or continued use of hepatotoxins such as alcohol. Future research should attempt to develop standardized and reproducible methods to assess liver drug concentration, complex drug interactions, and pharmacogenomics in humans to permit elucidation of the clinical pharmacology within the liver.
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Affiliation(s)
- Charles S Venuto
- Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY, USA.,AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Andrew H Talal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University at Buffalo, Buffalo, NY, USA
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Crisan D, Grigorescu MD, Radu C, Suciu A, Grigorescu M. Interferon-γ-inducible protein-10 in chronic hepatitis C: Correlations with insulin resistance, histological features & sustained virological response. Indian J Med Res 2018; 145:543-550. [PMID: 28862188 PMCID: PMC5663170 DOI: 10.4103/ijmr.ijmr_1410_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND & OBJECTIVES One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology. METHODS Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment-IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed. RESULTS A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR. INTERPRETATION & CONCLUSIONS Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection.
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Affiliation(s)
- Dana Crisan
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
| | - Mircea Dan Grigorescu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania
| | - Corina Radu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
| | - Alina Suciu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
| | - Mircea Grigorescu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
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Pre-vaccine plasma levels of soluble inflammatory indices negatively predict responses to HAV, HBV, and tetanus vaccines in HCV and HIV infection. Vaccine 2017; 36:453-460. [PMID: 29254840 DOI: 10.1016/j.vaccine.2017.12.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 11/29/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) and HIV infections are associated with impaired responses to neo-antigens contained in hepatitis A virus (HAV)/hepatitis B virus (HBV) vaccines, yet responsible mechanisms are unclear. METHODS ACTG 5232 and CFAR0910 were clinical trials where pre-vaccine levels of plasma IP10, IL-6, sCD163 and sCD14 were measured in viremic HCV- (n = 15) or HIV-infected participants (n = 24) and uninfected controls (n = 10). Accelerated dosing HAV/HBV vaccine and tetanus booster were administered and antibody response was measured at 0, 1, 3, 8, and 24 weeks. RESULTS Pre-vaccine plasma IP10, IL-6, and sCD14 levels were elevated in both HCV and HIV-infected participants, while sCD163 was also elevated in HCV-infected participants. Pre-immunization tetanus antibody levels were lower in HIV-infected than in uninfected participants, while vaccine induced antibody responses were intact in HCV and HIV-infected participants. After HAV/HBV vaccination, HCV and HIV-infected participants had lower and less durable HAV and HBV antibody responses than uninfected controls. Among HCV-infected participants, pre-vaccine plasma IP10, IL-6, sCD14, and sCD163 levels inversely correlated with HAV, HBV and tetanus antibody responses after vaccine. Low HAV/HBV vaccine responses in HIV-infected participants prohibited assessment of immune correlates. CONCLUSIONS During HCV and HIV infection markers of systemic inflammation reflect immune dysfunction as demonstrated by poor response to HAV/HBV neo-antigen vaccine.
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Jiménez-Sousa MÁ, Gómez-Moreno AZ, Pineda-Tenor D, Medrano LM, Sánchez-Ruano JJ, Fernández-Rodríguez A, Artaza-Varasa T, Saura-Montalban J, Vázquez-Morón S, Ryan P, Resino S. CXCL9-11 polymorphisms are associated with liver fibrosis in patients with chronic hepatitis C: a cross-sectional study. Clin Transl Med 2017; 6:26. [PMID: 28755163 PMCID: PMC5533694 DOI: 10.1186/s40169-017-0156-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/23/2017] [Indexed: 02/06/2023] Open
Abstract
Background and aims CXCL9-11 polymorphisms are related to various infectious diseases, including hepatitis C virus (HCV) infection. In this study, we analyzed the association between CXCL9-11 polymorphisms and liver fibrosis in HCV-infected patients. Methods We performed a cross-sectional study in 389 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using the Sequenom’s MassARRAY platform. The primary outcome variable was the liver stiffness measurement (LSM). We established three cut-offs of LSM: LSM ≥ 7.1 kPa (F ≥ 2—significant fibrosis), LSM ≥ 9.5 kPa (F ≥ 3—advanced fibrosis), and LSM ≥ 12.5 kPa (F4—cirrhosis). Results Recessive, overdominant and codominant models of inheritance showed significant values, but the overdominant model was the best fitting our data. In this case, CXCL9 rs10336 AG, CXCL10 rs3921 CG and CXCL11 rs4619915 AG were mainly associated with lower values of LSM [(adjusted GMR (aGMR) = 0.85 (p = 0.005), aGMR = 0.84 (p = 0.003), and aGMR = 0.84 (p = 0.003), respectively]. Patients with CXCL9 rs10336 AG genotype had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.59 (p = 0.016)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.54 (p = 0.010)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.56 (p = 0.043)]. Patients with CXCL10 rs3921 CG or CXCL11 rs4619915 AG genotypes had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.56 (p = 0.008)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.55 (p = 0.013)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.57 (p = 0.051)]. Additionally, CXCL9-11 polymorphisms were related to lower liver stiffness under a codominant model of inheritance, being the heterozygous genotypes also protective against hepatic fibrosis. In the recessive inheritance model, the CXCL9 rs10336 AA, CXCL10 rs3921 CC and CXCL11 rs4619915 AA were associated with higher LSM values [(adjusted GMR (aGMR) = 1.19 (p = 0.030), aGMR = 1.21 (p = 0.023), and aGMR = 1.21 (p = 0.023), respectively]. Moreover, patients with CXCL9 rs10336 AA genotype had higher odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 1.83 (p = 0.044)] and advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.85 (p = 0.045)]. Furthermore, patients with CXCL10 rs3921 CC or CXCL11 rs4619915 AA genotypes had higher odds of advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.89 (p = 0.038)]. Conclusions CXCL9-11 polymorphisms were related to likelihood of having liver fibrosis in HCV-infected patients. Our data suggest that CXCL9-11 polymorphisms may play a significant role against the progression of CHC and could help prioritize antiviral therapy.
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Affiliation(s)
- María Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | | | - Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital Universitario de Fuenlabrada, Madrid, Spain
| | - Luz Maria Medrano
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | | | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | | | | | - Sonia Vázquez-Morón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Pablo Ryan
- Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Mascia C, Vita S, Zuccalà P, Marocco R, Tieghi T, Savinelli S, Rossi R, Iannetta M, Pozzetto I, Furlan C, Mengoni F, Mastroianni CM, Vullo V, Lichtner M. Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon. PLoS One 2017. [PMID: 28636655 PMCID: PMC5499435 DOI: 10.1371/journal.pone.0179400] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background and aims Increased levels of chemokine interferon-gamma (IFN-γ)-inducible protein-10
(CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported
in HCV infection. The aim of this study was to compare, sCD163 and sCD14
levels in HCV-infected patients undergoing direct acting antiviral
(DAA)-containing regimens with or without interferon (IFN). Methods sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma
samples from 25 HCV-infected patients undergoing IFN-based treatment plus
telaprevir or boceprevir and 28 HCV infected subjects treated with DAA
IFN-free regimens. Twenty-five healthy donors (HD) were included as
controls. Results At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected
patients than in HD. CXCL10 and sCD163 levels were significantly decreased
in responder (R) patients who achieved sustained virological response (SVR),
with both IFN-based and IFN-free regimens, while they were persistently
elevated in non-responders (NR) patients who stopped IFN-based treatments
because of failure or adverse events. Conversely, sCD14 levels were
apparently unchanged during therapy, but at the end of treatment the levels
reached normal ranges. Comparing the two regimens, the extent of CXCL10
reduction was more pronounced in patients undergoing DAA IFN-free therapies,
whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were
significantly higher in NR than in R patients, while in the IFN-free
treatment group also patients with high sCD163 plasma levels obtained SVR.
At the end of therapy, even if the biomarkers were largely decreased, their
levels remained significantly higher compared to HD. Only in the early
fibrosis stages, sCD163 values tended to normalize. Conclusions These results indicate that IFN-free regimens including newer DAA induce an
early and marked decrease in circulating inflammatory biomarkers. However,
the full normalization of biomarkers was not obtained, especially in
patients with advanced fibrosis, thus underlying the need for a treatment in
the early stages of HCV infection.
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Affiliation(s)
- Claudia Mascia
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- * E-mail:
| | - Serena Vita
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Paola Zuccalà
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Raffaella Marocco
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Tiziana Tieghi
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Stefano Savinelli
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Raffaella Rossi
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Marco Iannetta
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Irene Pozzetto
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Caterina Furlan
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Fabio Mengoni
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy
- Infectious Diseases Unit, Sapienza University, S. M. Goretti Hospital,
Latina, Italy
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Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C. PLoS One 2017; 12:e0179094. [PMID: 28614389 PMCID: PMC5470700 DOI: 10.1371/journal.pone.0179094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/23/2017] [Indexed: 02/08/2023] Open
Abstract
Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.
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Neesgaard B, Ruhwald M, Weis N. Inducible protein-10 as a predictive marker of antiviral hepatitis C treatment: A systematic review. World J Hepatol 2017; 9:677-688. [PMID: 28588752 PMCID: PMC5437612 DOI: 10.4254/wjh.v9.i14.677] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/30/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate interferon-γ-inducible protein-10’s (IP-10) potential to anticipate rapid (RVR)- and sustained virological responses (SVR) to chronic hepatitis C (CHC) treatment.
METHODS We included case series examining RVR or SVR in relation to 24 or 48 wk treatment for CHC, in patients treatment free for at least six months, with genotype 1 or 4, and in relation to 24 wk treatment for genotype 2 and 3, with pegylated interferon in combination with ribavirin. Patients had to have both a baseline IP-10 level as well as a hepatitis C virus (HCV)-RNA determination 4 wk after treatment initiation or 24 wk after end of treatment. Studies including patients with liver diseases other than CHC, human immunodeficiency virus-infection, treatment with immunosuppresents or cytostatica, alcohol dependency or active intravenous drug-use were excluded. We found 81 articles by searching the MEDLINE and EMBASE databases. Eight studies were eligible for inclusion. Their quality were assesed using an 18 point checklist for case series, developed using a modified Delphi technique. Information was extracted from the articles, and no raw data was requisitioned. The review protocol was registered at the International Prospective Register of Systematic Reviews (reg. number: CRD42014008736).
RESULTS Three studies reported on baseline IP-10 level in association with RVR. A signigficant association was found for HCV genotype 1 infection by two studies. Only two studies reported on HCV genotype 4 infected and genotype 2 and 3 infected patients, respectively. A trend was seen for an association between RVR and baseline IP-10 for genotype 4, while no association was found for genotype 2 and 3. Seven studies provided information regarding baseline IP-10 and SVR. Following the pattern regarding rapid virological response all five studies examining SVR in relation to baseline IP-10 levels for HCV, genotype 1 infected patients showed a significant association. Likewise a significant association was seen for HCV, genotype 4 infected, while no association was found for HCV, genotype 2 and 3 infected. Though only two studies examined the assosiation for HCV genotype 4 infected and HCV genotype 2 and 3 infected respectively.
CONCLUSION We found indications of a possible association between baseline IP-10 level and virological responses in patients with CHC genotype 1 and 4.
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Lin WHW, Nelson AN, Ryon JJ, Moss WJ, Griffin DE. Plasma Cytokines and Chemokines in Zambian Children With Measles: Innate Responses and Association With HIV-1 Coinfection and In-Hospital Mortality. J Infect Dis 2017; 215:830-839. [PMID: 28119485 PMCID: PMC5388292 DOI: 10.1093/infdis/jix012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 01/05/2017] [Indexed: 12/19/2022] Open
Abstract
To identify immune factors present during the acute rash phase of measles and associations with outcome and human immunodeficiency virus type 1 (HIV-1) coinfection, we measured the plasma levels of 22 cytokines and chemokines in Zambian children hospitalized with measles (n = 148) and control children (n = 44). Children with measles had higher levels of innate cytokines tumor necrosis factor (TNF) α, interleukin 1β (IL-1β), interleukin 18, and interleukin 6; chemokines CCL2, CCL4, CCL11, CCL22, CXCL8, and CXCL10; and T-cell cytokines interferon γ, and interleukin 2, 10, and 17. Children who died in the hospital had higher levels of TNF-α, IL-1β, interleukin 12p70; CCL2, CCL4, CCL13, CCL17, CXCL8, CXCL10; and interleukin 2 and interferon γ than children who survived, and lower levels of interleukin 4. Children coinfected with HIV-1 had higher levels of TNF-α and IL-1β than HIV-uninfected children with measles, and lower levels of interleukin 4 and 5. Therefore, acute measles was characterized by activation of macrophages and T cells producing type 1, but not type 2, cytokines, which was more pronounced in fatal disease.
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Affiliation(s)
- Wen-Hsuan W Lin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
| | - Ashley N Nelson
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
| | - Judith J Ryon
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
| | - William J Moss
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Diane E Griffin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
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Komolmit P, Charoensuk K, Thanapirom K, Suksawatamnuay S, Thaimai P, Chirathaworn C, Poovorawan Y. Correction of vitamin D deficiency facilitated suppression of IP-10 and DPP IV levels in patients with chronic hepatitis C: A randomised double-blinded, placebo-control trial. PLoS One 2017; 12:e0174608. [PMID: 28376103 PMCID: PMC5380326 DOI: 10.1371/journal.pone.0174608] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/12/2017] [Indexed: 12/31/2022] Open
Abstract
UNLABELLED Vitamin D deficiency was common among patients with chronic hepatitis C (CHC) and had negative influence on treatment outcome. Correction of vitamin D deficiency improved treatment response. Interferon gamma-induced protein 10 (IP-10) and enzyme dipeptidyl peptidase-4 (DPP IV) involved in inflammatory responses in CHC. Their higher levels at pretreatment of CHC could predict poorer responses. Vitamin D suppressed expression of IP-10 from monocytes in vitro. In CHC patients, DPP IV involved in IP-10 regulation. We hypothesized that correction of vitamin D insufficiency or deficiency in CHC patients might restore immune dysregulation through a pathway linked to the TH1/Th2 cytokines, IP-10 or DPP IV. We conducted a double-blind, placebo-controlled trial. 80 CHC patients with vitamin D levels less than 30 ng/mL were assigned to receive vitamin D (40) or placebo (40) supplements for 6 weeks. The levels of 25-hydroxyvitamin D [25(OH)D], Th1/Th2 cytokines, IP-10 and DPP IV were measured at baseline and at the 6th week. At the end of study, the mean 25(OH)D level in vitamin D group was significantly increased and normalised. There were no changes in the level of Th1/Th2 cytokines. Our important finding revealed that upon correction of vitamin D insufficiency or deficiency, the serum IP-10 and DPP IV levels were decreased significantly as compare to the placebo group (delta changes; 83.27 vs -133.80; 95% CI [-326.910, -40.758], p = 0.0125, and 271.04 vs -518.69; 95% CI [-1179,15, -59.781], p = 0.0305, respectively. As previous evidences suggested that each factor individually influenced and predicted outcome of CHC treatment. Our results offer a new insight and help to piece the puzzle of vitamin D deficiency, IP-10 and DPP IV together in CHC. TRIAL REGISTRATION Thai Clinical Trials Registry TCTR20160429001.
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Affiliation(s)
- Piyawat Komolmit
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Kriangsak Charoensuk
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Division of Gastroenterology, Department of Internal medicine, Buddhachinaraj Hospital School of Medicine, Phitsanulok, Thailand
| | - Kessarin Thanapirom
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Panarat Thaimai
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Chintana Chirathaworn
- Division of Immunology, Department of Microbiology, Chulalongkorn university, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Childs K, Merritt E, Considine A, Sanchez-Fueyo A, Agarwal K, Martinez-Llordella M, Carey I. Immunological Predictors of Nonresponse to Directly Acting Antiviral Therapy in Patients With Chronic Hepatitis C and Decompensated Cirrhosis. Open Forum Infect Dis 2017; 4:ofx067. [PMID: 28584852 PMCID: PMC5450903 DOI: 10.1093/ofid/ofx067] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 03/31/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sustained virological response rates (SVRs) to directly acting antiviral (DAA) therapy for hepatitis C virus (HCV) are lower in decompensated cirrhosis. Markers of innate immunity predict nonresponse to interferon-based HCV treatment; however, whether they are associated with the response to DAAs in patients with decompensation is not known. METHODS Information on demographics, adherence, viral kinetics, and resistance were gathered prospectively from a cohort with decompensated cirrhosis treated with 12 weeks of DAAs. C-X-C motif chemokine-10 (CXCL-10) level and T-cell and natural killer (NK) cell phenotype were analyzed pretreatment and at 4 and 12 weeks of treatment. RESULTS Of 32 patients, 24 of 32 (75%) achieved SVR (responders). Eight of 32 (25%) experienced relapse after the end of treatment (nonresponders). There were no differences in demographics or adherence between groups. Nonresponders had higher CXCL-10; 320 pg/mL (179461) vs 109 pg/mL (88170) in responders (P < .001) and differential CXCL-10 dynamics. Nonresponders had lower NK cell frequency, higher expression of activation receptor NKp30, and lower frequency of the NK subset CD56-CD16+. CONCLUSIONS Nonresponders to DAAs displayed a different NK phenotype and CXCL-10 profile to responders. Nonresponders did not have poorer adherence or baseline virological resistance, and this shows that immunological parameters are associated with treatment response to interferon-free treatment for HCV in individuals with decompensated cirrhosis.
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Affiliation(s)
- Kate Childs
- Liver Sciences, King's College London, United Kingdom; and
| | - Elliot Merritt
- Liver Sciences, King's College London, United Kingdom; and
| | - Aisling Considine
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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van Houten CB, de Groot JAH, Klein A, Srugo I, Chistyakov I, de Waal W, Meijssen CB, Avis W, Wolfs TFW, Shachor-Meyouhas Y, Stein M, Sanders EAM, Bont LJ. A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study. THE LANCET. INFECTIOUS DISEASES 2017; 17:431-440. [DOI: 10.1016/s1473-3099(16)30519-9] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/11/2016] [Accepted: 10/28/2016] [Indexed: 12/22/2022]
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Zhang M, Jiang Y, Xiao X, Peng M, Peng F, Gong G. Differences in IP‑10, TLR4 and IRF5/3 between SVR and non‑SVR HCV‑1 patients treated with PEG‑IFN and ribavirin. Mol Med Rep 2017; 15:2318-2324. [PMID: 28259968 DOI: 10.3892/mmr.2017.6229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 11/01/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate alterations in Toll‑like receptor 4 (TLR4), interferon regulatory factor 5 (IRF5) and interferon‑γ‑inducible protein‑10 (IP‑10), and evaluate whether these factors may be associated with a sustained virological response (SVR) among patients with hepatitis C virus genotype‑1 (HCV‑1) who were treated with peginterferon plus ribavirin (PEG‑IFN‑RBV). A total of 31 Chinese patients infected with HCV‑1 were enrolled in the present study and 25 patients obtained SVR. The expression levels of IP‑10 declined significantly during PEG‑IFN‑RBV therapy at the 24 and 48 week time‑points, compared with the baseline (P<0.005, 0.001 and 0.001, respectively). In addition, it was observed that IRF5 mRNA expression and the number of TLR4+ peripheral blood mononuclear cells exhibited similar correlations with IP‑10 concentration (R2=0.0726, P=0.001, R2=0.1634, P<0.0001, respectively) in the SVR group patients; however, these correlations were not observed to be present in the non‑SVR group patients. In conclusion, the results of the present study suggest that marked alterations in IP‑10, TLR4 and IRF5 expression may serve as indicators for the development of SVR in patients with HCV‑1 treated with PEG‑IFN‑RBV.
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Affiliation(s)
- Min Zhang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yongfang Jiang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Xinqiang Xiao
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Milin Peng
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Feng Peng
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Guozhong Gong
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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Wang Y, Yu W, Shen C, Wang W, Zhang L, Liu F, Sun H, Zhao Y, Che H, Zhao C. Predictive Value of Serum IFN-γ inducible Protein-10 and IFN-γ/IL-4 Ratio for Liver Fibrosis Progression in CHB Patients. Sci Rep 2017; 7:40404. [PMID: 28067328 PMCID: PMC5220308 DOI: 10.1038/srep40404] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 12/06/2016] [Indexed: 12/17/2022] Open
Abstract
Noninvasive serum markers for assessment of liver fibrosis in chronic hepatitis B (CHB) patients have not been well-studied. The present study was to evaluate the predictive value of serum interferon gamma-inducible protein-10 (IP-10/CXCL10) and the interferon (IFN)-γ/interleukin (IL)-4 ratio for liver fibrosis progression in CHB patients. A total of 180 CHB patients were categorized into four groups: no fibrosis, mild fibrosis, moderate fibrosis, and severe fibrosis. Serum and intrahepatic levels of IP-10, IFN-γ, and IL-4 were examined, from which the IFN-γ/IL-4 ratio was calculated. We found that the serum IP-10 levels were positively correlated with the severity of liver fibrosis, whereas the IFN-γ/IL-4 ratio was negatively associated with the progression of hepatic fibrosis. Multivariate logistic regression analysis revealed that the serum IP-10 was an independent predictor for significant fibrosis. For predicting significant fibrosis, the IP-10 cut-off value of 300 ng/mL had a sensitivity of 92.7% and a specificity of 68.6%. When the IP-10 level was combined with the IFN-γ/IL-4 ratio, the specificity and positive predictive value were 93.8% and 94.6%, respectively; thus, the discriminatory ability was much improved. In conclusion, the serum IP-10 level and the IFN-γ/IL-4 ratio have great potential to predict significant fibrosis among CHB patients.
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Affiliation(s)
- Yadong Wang
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Weiyan Yu
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Chuan Shen
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wei Wang
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Zhang
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Fang Liu
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Hui Sun
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yajuan Zhao
- Division of Liver Disease, The Infectious Disease Hospital of Handan City, Handan, Hebei, China
| | - Honghao Che
- Department of Gastroenterology and Hepatology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei, China
| | - Caiyan Zhao
- Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Büsch K, Waldenström J, Lagging M, Aleman S, Weiland O, Kövamees J, Duberg AS, Söderholm J. Prevalence and comorbidities of chronic hepatitis C: a nationwide population-based register study in Sweden. Scand J Gastroenterol 2017; 52:61-68. [PMID: 27598393 DOI: 10.1080/00365521.2016.1228119] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
PURPOSE The aim of this study was to estimate the prevalence of physician-diagnosed and registered chronic hepatitis C (CHC), and to estimate the reported frequencies of Charlson comorbidities compared with matched comparators from the general population. MATERIALS AND METHODS Patients were identified according to ICD codes for CHC in the Swedish National Patient Register (1997-2013). Prevalence was estimated according to different patient identification algorithms and for different subgroups. Charlson comorbidities were ascertained from the same register and compared with age/sex/county of residence matched general population comparators. RESULTS A total of 34,633 individuals with physician-diagnosed CHC were alive in Sweden in 2013 (mean age, 49 years; 64% men), corresponding to a physician-diagnosed prevalence of 0.36%. The prevalence varied by case definition (0.22%-0.36%). The estimate dropped to 0.14% for monitored CHC disease (defined as ≥1 CHC-related visit in 2013). Overall, 41.3% of the CHC patients had ≥1 physician-registered Charlson comorbidity; the most common was liver diseases (22.1%). Compared with matched comparators from the general population (n = 171,338), patients with CHC had more physician-diagnosed and registered diseases such as chronic pulmonary disease (10.2% vs. 4.0%), diabetes (10.6% vs. 5.5%) and liver-related cancer (1.3% vs. 0.2%; all p < .01). No information on behavioural factors, such as smoking, alcohol consumption or on-going illicit drug use, was available. CONCLUSION The physician-diagnosed prevalence of CHC was slightly lower than previously reported estimates, and varied by case definition. The additional comorbidities observed in the CHC group should be taken into consideration, as these comorbidities add to the disease burden.
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Affiliation(s)
- Katharina Büsch
- a AbbVie AB , Stockholm , Sweden.,b Department of Medicine , Karolinska Institutet , Stockholm , Sweden.,h Department of Laboratory Medicine, Division of Clinical Microbiology , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden
| | - Jesper Waldenström
- c Department of Infectious Medicine , Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden
| | - Martin Lagging
- c Department of Infectious Medicine , Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden
| | - Soo Aleman
- d Department of Infectious Diseases , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden.,e Department of Gastroenterology and Hepatology , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden
| | - Ola Weiland
- f Department of Medicine Huddinge, Division of Infectious Diseases , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden
| | | | - Ann-Sofi Duberg
- g Department of Infectious Diseases, Faculty of Medicine and Health , Örebro University , Örebro , Sweden
| | - Jonas Söderholm
- a AbbVie AB , Stockholm , Sweden.,h Department of Laboratory Medicine, Division of Clinical Microbiology , Karolinska Institutet, Karolinska University Hospital , Stockholm , Sweden
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Abstract
INTRODUCTION By virtue of its specificity for chemokines induced in Th1-associated pathologies, CXCR3 has attracted considerable attention as a target for therapeutic intervention. Several pharmacologically distinct small molecules with in vitro and in vivo potency have been described in the literature, although to date, none have shown efficacy in clinical trials. Areas covered: In this article, the author outlines the rationale for targeting CXCR3 and discusses the potential pitfalls in targeting receptors in poorly understood areas of chemokine biology. Furthermore, they cover emerging therapeutic areas outside of the 'traditional' Th1 arena in which CXCR3 antagonists may ultimately bear fruit. Finally, they discuss the design of recently discovered small molecules targeting CXCR3. Expert opinion: CXCR3 and its ligands appear to play roles in a multitude of diverse diseases in humans. In vitro studies suggest that CXCR3 is inherently 'druggable' and that potent, efficacious small molecules targeting CXCR3 antagonists will find a clinical niche. However, the well-trodden path to failure of small molecule chemokine receptor antagonists in clinical trials suggests that a cautious approach should be undertaken. Ideally, unequivocal evidence elucidating the precise role of CXCR3 should be obtained before targeting the receptor in a particular disease cohort.
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Affiliation(s)
- James E Pease
- a Inflammation, Repair & Development Section, National Heart & Lung Institute, Faculty of Medicine , Imperial College London , London , UK
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Yamagiwa Y, Asano M, Kawasaki Y, Korenaga M, Murata K, Kanto T, Mizokami M, Masaki N. Pretreatment serum levels of interferon-gamma-inducible protein-10 are associated with virologic response to telaprevir-based therapy. Cytokine 2016; 88:29-36. [PMID: 27541605 DOI: 10.1016/j.cyto.2016.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 07/03/2016] [Accepted: 07/05/2016] [Indexed: 01/16/2023]
Abstract
AIM Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. METHODS In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. RESULTS We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. CONCLUSIONS Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.
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Affiliation(s)
- Yoko Yamagiwa
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
| | - Mai Asano
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Youhei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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C-X-C motif chemokine 10 in non-alcoholic steatohepatitis: role as a pro-inflammatory factor and clinical implication. Expert Rev Mol Med 2016; 18:e16. [PMID: 27669973 DOI: 10.1017/erm.2016.16] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD and causes subsequent pathological changes including cirrhosis and hepatocellular carcinoma. Inflammation is the key pathological change in NASH and involves a series of cytokines and chemokines. The C-X-C motif chemokine 10 (CXCL10), which is known as a pro-inflammation chemokine, was recently proven to play a pivotal role in the pathogenesis of NASH. Hepatic CXCL10 is mainly secreted by hepatocytes and liver sinusoidal endothelium. By binding to its specific receptor CXCR3, CXCL10 recruits activated CXCR3+ T lymphocytes and macrophages to parenchyma and promotes inflammation, apoptosis and fibrosis. The circulating CXCL10 level correlates with the severity of lobular inflammation and is an independent risk factor for NASH patients. Thus, CXCL10 may be both a potential prognostic tool and a therapeutic target for the treatment of patients with NASH. The aim of this review is to highlight the growing advances in basic knowledge and clinical interest of CXCL10 in NASH to propagate new insights into novel pharmacotherapeutic avenues.
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Chen Yi Mei SLG, Burchell J, Skinner N, Millen R, Matthews G, Hellard M, Dore GJ, Desmond PV, Sundararajan V, Thompson AJ, Visvanathan K, Sasadeusz J. Toll-like Receptor Expression and Signaling in Peripheral Blood Mononuclear Cells Correlate With Clinical Outcomes in Acute Hepatitis C Virus Infection. J Infect Dis 2016; 214:739-47. [PMID: 27284092 DOI: 10.1093/infdis/jiw235] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 05/23/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma. RESULTS We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001). CONCLUSIONS These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.
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Affiliation(s)
- Swee Lin G Chen Yi Mei
- Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Jodie Burchell
- Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne
| | - Narelle Skinner
- Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Rosie Millen
- Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Gail Matthews
- Kirby Institute, University of New South Wales, Sydney
| | - Margaret Hellard
- Centre for Population Health, Burnet Institute Department of Infectious Diseases, the Alfred Hospital, Melbourne, Australia
| | | | | | - Vijaya Sundararajan
- Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne
| | - Alexander J Thompson
- Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Kumar Visvanathan
- Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Joe Sasadeusz
- Department of Infectious Diseases, Royal Melbourne Hospital
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Zhang R, Shao C, Huo N, Li M, Xu X. Association of IL28B Genotypes and Baseline Serum Interferon-γ-Inducible- Protein-10 Levels with Treatment Response in Hepatitis C Virus Patients in China. Gut Liver 2016; 10:446-455. [PMID: 26470765 PMCID: PMC4849699 DOI: 10.5009/gnl15162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/19/2015] [Accepted: 05/28/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Several studies have demonstrated that serum interferon-γ-inducible-protein-10 (IP-10) levels at baseline and single nucleotide polymorphisms (SNPs) near the IL28B gene were associated with viral response and treatment outcomes. Our purpose was to assess the combination of pretreatment IP-10 levels with IL28B SNPs as predictors of treatment response to pegylated interferon α-2a plus ribavirin in patients infected with genotype 1 hepatitis C virus in China. METHODS Seventy-two patients with chronic hepatitis C without fibrosis/cirrhosis were enrolled in the study. The virologic parameters and baseline serum IP-10 levels were determined. IL-28B genotypes were determined by sequencing. RESULTS In this cohort, serum baseline IP-10 levels lower than 426.7 pg/mL could predict rapid virological response/ sustained virological response (SVR). Patients carrying favorable IL28B SNP genotypes had higher SVRs than did those carrying unfavorable variants (IL28B rs12979860, p=0.002; IL28B rs8099917, p=0.020). Combining both baseline IP- 10 and IL28B SNPs could improve the prediction of SVR in favorable allele carriers of IL28B, rs12979860 CC and rs8099917 TT. Serum baseline IP-10 levels and IL28B genotypes were independent predictors of SVR. CONCLUSIONS Our study shows that the combination of baseline serum IP-10 levels and the determination of IL28B SNPs increase the predictability of SVR rates in this cohort. (Gut Liver 2016;10446-455).
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Affiliation(s)
- Renwen Zhang
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Cuiping Shao
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Na Huo
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Minran Li
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
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Waldenström J, Westin J, Nyström K, Christensen P, Dalgard O, Färkkilä M, Lindahl K, Nilsson S, Norkrans G, Krarup H, Norrgren H, Rauning Buhl M, Stenmark S, Lagging M. Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection. PLoS One 2016; 11:e0155142. [PMID: 27167219 PMCID: PMC4864304 DOI: 10.1371/journal.pone.0155142] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 03/20/2016] [Indexed: 01/10/2023] Open
Abstract
In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naïve patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-α (pegIFN-α), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-α, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-α. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log10 IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log10 IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-α and thus shortened treatment duration (P<0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P<0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an anti-viral effect differently regulated across IL28B genotypes.
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Affiliation(s)
- Jesper Waldenström
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Johan Westin
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kristina Nyström
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peer Christensen
- Department of Infectious Diseases, University of Southern Denmark, Odense, Denmark
| | - Olav Dalgard
- Department of Infectious Diseases, Akershus University Hospital, Oslo, Norway
| | - Martti Färkkilä
- Department of Gastroenterology, Helsinki University, Helsinki, Finland
| | - Karin Lindahl
- Department of Infectious Diseases, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Gunnar Norkrans
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Hans Norrgren
- Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden
| | - Mads Rauning Buhl
- Department of Infectious Diseases, Aarhus University, Aarhus, Denmark
| | - Stephan Stenmark
- Department of Communicable Disease Control Västerbotten, Umeå, Sweden
| | - Martin Lagging
- Department of Infectious Medicine, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
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Willemse SB, Jansen L, de Niet A, Sinnige MJ, Takkenberg RB, Verheij J, Kootstra NA, Reesink HW. Intrahepatic IP-10 mRNA and plasma IP-10 levels as response marker for HBeAg-positive chronic hepatitis B patients treated with peginterferon and adefovir. Antiviral Res 2016; 131:148-55. [PMID: 27155352 DOI: 10.1016/j.antiviral.2016.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/27/2016] [Accepted: 05/03/2016] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Interferon-y-inducible protein-10 (IP-10), also called CXCL10, is produced by different types of cells such as monocytes, neutrophils and hepatocytes. IP-10 functions as an inflammatory cytokine, which after binding to its receptor CXCR3, expressed on T-lymphocytes, leads to immune activation. We aimed to establish if IP-10 expression in liver tissue and in plasma of chronic hepatitis B (CHB) patients correlated with each other and further to investigate if IP-10 levels before and during therapy with peginterferon and adefovir could predict treatment outcome in CHB patients. PATIENTS AND METHODS A total of 86 CHB patients (41 HBeAg-positive and 45 HBeAg-negative) received combination therapy of peginterferon and adefovir for 48 weeks. Combined Response (CR) (HBeAg-negativity, HBV-DNA ≤ 2000 IU/mL, ALT normalization) and non-response (NR) were assessed at Week 72. Plasma IP-10 levels were measured at baseline and during treatment at Day 3 (D3) and Week 1 (W1). Pre-treatment liver biopsies from 40 of 86 patients were obtained and stored in liquid nitrogen for the analysis of intrahepatic IP-10 mRNA expression. RESULTS CR was achieved in 14/41 HBeAg-positive and 17/45 HBeAg-negative patients. Mean baseline plasma IP-10 levels were significantly higher in HBeAg-positive patients with CR than NR (3.20 vs 3.00 log pg/mL p = 0.03); but not in HBeAg-negative patients. Baseline IP-10 levels correlated with ALT-levels in HBeAg-positive and -negative patients (both p < 0.001), and with a decline of HBsAg-levels of ≥0.5 log IU/mL at Week 12 in HBeAg-positive patients (p = 0.001). Plasma IP-10 levels were associated with intrahepatic IP-10 mRNA expression, however, more strongly in HBeAg-positive (R = 0.79, p < 0.001) than in HBeAg-negative patients (R = 0.53, p = 0.011). IP-10 levels only correlated with HAI-scores in HBeAg-positive patients (R = 0.40 p = 0.025). Mean plasma IP-10 levels of both HBeAg-positive and -negative patients increased significantly at D3 compared to baseline (+0.30 log pg/mL p = 0.003), to then decline subsequently at W1 to a level still significantly higher than baseline (+0.14 log pg/mL p < 0.001). The increase of IP-10 was significantly higher in HBeAg-positive patients with NR than in those with CR (+0.35 versus +0.11 log pg/mL p = 0.003). CONCLUSIONS Baseline plasma IP-10 levels and IP-10 mRNA expression in the liver are correlated with each other, suggesting that plasma IP-10 reflects intrahepatic immune activation. Higher IP-10 levels at baseline seem to be associated with CR in HBeAg-positive patients treated with peginterferon and adefovir, but not in HBeAg-negative patients.
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Affiliation(s)
- S B Willemse
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands.
| | - L Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
| | - A de Niet
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
| | - M J Sinnige
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands; Department of Experimental Immunology, Academic Medical Center, The Netherlands
| | - R B Takkenberg
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
| | - J Verheij
- Department of Pathology, Academic Medical Center, The Netherlands
| | - N A Kootstra
- Department of Experimental Immunology, Academic Medical Center, The Netherlands
| | - H W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
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Hajarizadeh B, Lamoury FM, Feld JJ, Amin J, Keoshkerian E, Matthews GV, Hellard M, Dore GJ, Lloyd AR, Grebely J, Applegate TL. Alanine aminotransferase, HCV RNA levels and pro-inflammatory and pro-fibrogenic cytokines/chemokines during acute hepatitis C virus infection. Virol J 2016; 13:32. [PMID: 26911712 PMCID: PMC4765111 DOI: 10.1186/s12985-016-0482-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/02/2016] [Indexed: 12/12/2022] Open
Abstract
Background This study assessed the association of alanine-aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels with pro-inflammatory and pro-fibrogenic cytokines and chemokines during acute HCV infection to provide further insight into the potential HCV immunopathogenesis. Methods Participants in the ATAHC study, a prospective study of recent HCV infection, with detectable HCV RNA at the time of HCV detection were included. Plasma levels of 27 cytokines and chemokines were measured and their correlation with ALT and HCV RNA levels were assessed. Log10 transformed cytokines and ALT values were used in the analysis. Results Among 117 individuals, the plasma levels of interferon-gamma inducible protein-10 (IP-10) and macrophage inflammatory protein-1beta (MIP-1β) were positively correlated with ALT levels (IP-10: r = 0.42, P < 0.001; MIP-1β: r = 0.29, P = 0.001) and HCV RNA levels (IP-10: rs = 0.44, P < 0.001; MIP-1β: rs = 0.43, P < 0.001). Using linear regression, after adjusting for sex, age, infection duration, symptomatic infection, HIV co-infection, interferon-lambda rs12979860 genotype, HCV genotype, and assay run, higher ALT levels (β = 0.20; 95 % CI: 0.07, 0.32; P = 0.002) and HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; β = 0.16; 95 % CI: 0.03, 0.28; P = 0.014) were independently associated with higher IP-10 levels. HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; β = 0.16; 95 % CI: 0.01, 0.31; P = 0.036) were associated with higher MIP-1β levels. Conclusions During acute HCV infection, high ALT and HCV RNA levels were associated with increased IP-10 levels, while high HCV RNA levels were also associated with increased MIP-1β levels. These data suggest that IP-10 and MIP-1β may have a role in HCV immuno-pathogenesis starting early in acute HCV infection. Electronic supplementary material The online version of this article (doi:10.1186/s12985-016-0482-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Behzad Hajarizadeh
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - François Mj Lamoury
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - Jordan J Feld
- Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Canada.
| | - Janaki Amin
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - Elizabeth Keoshkerian
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, Australia.
| | - Gail V Matthews
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia. .,HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia.
| | | | - Gregory J Dore
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia. .,HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, Australia.
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, Australia.
| | - Jason Grebely
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
| | - Tanya L Applegate
- The Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, 2052, Australia.
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Bartolomé J, Castillo I, Quiroga JA, Carreño V. Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection. J Med Virol 2016; 88:268-74. [PMID: 26147900 DOI: 10.1002/jmv.24322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2015] [Indexed: 12/31/2022]
Abstract
Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5) ± 5.8 × 10(4) vs. 4.1 × 10(5) ± 5.9 × 10(4) copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C.
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Affiliation(s)
- Javier Bartolomé
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
| | | | | | - Vicente Carreño
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
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Karakhanova S, Oweira H, Steinmeyer B, Sachsenmaier M, Jung G, Elhadedy H, Schmidt J, Hartwig W, Bazhin AV, Werner J. Interferon-γ, interleukin-10 and interferon-inducible protein 10 (CXCL10) as serum biomarkers for the early allograft dysfunction after liver transplantation. Transpl Immunol 2015; 34:14-24. [PMID: 26658573 DOI: 10.1016/j.trim.2015.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 11/14/2015] [Accepted: 12/02/2015] [Indexed: 01/29/2023]
Abstract
Orthotopic liver transplantation (LTP) is nowadays a standard procedure, and provides the chance of survival of patients with end-stage non-treatable chronic liver disease or acute liver failure. Despite long-term survival with a good quality of life in the majority of patients, about 20% develop early allograft dysfunction (EAD), which leads to death or the need for re-transplantation. Therefore, the early diagnosis of EAD and evaluation of its risk factors are very important. Many primary pathological processes leading to EAD are accompanied by the release of different mediators and by a change of biochemical parameters detectable in the peripheral blood. The aim of this study was to investigate cytokines as well as soluble mediators in the serum of patients with and without EAD from our LTP bank, and to evaluate their predictive and prognostic values for EAD. We demonstrated for the first time that the level of IFNγ during the nearest preoperative period may serve as a predictive parameter for EAD. We additionally found that IL-10 and CXCL10 (IP-10) levels in the early postoperative period can be prognostic for EAD. We believe our data expand the spectrum of predictive and prognostic parameters for EAD in LTP.
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Affiliation(s)
- Svetlana Karakhanova
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
| | - Hani Oweira
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Beate Steinmeyer
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Milena Sachsenmaier
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Gregor Jung
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Hazem Elhadedy
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Jan Schmidt
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany; General and Visceral Surgery Center, 8002 Zurich, Switzerland
| | - Werner Hartwig
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany
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Prinapori R, Sticchi L, Alicino C, Del Puente F, Mazzarello G, Alessandrini A, Signori A, Icardi G, Bruzzone B, Viscoli C, Di Biagio A. Role of HCV-RNA decay and IP-10 levels after 48 hours of standard HCV therapy as predictors of rapid virological response. Clin Res Hepatol Gastroenterol 2015; 39:705-10. [PMID: 26070571 DOI: 10.1016/j.clinre.2015.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 03/25/2015] [Accepted: 04/15/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVES Rapid virological response (RVR) is a critical end-point in the era of the new direct-acting antiviral agents (DAA). The aim of this study was to evaluate the predictive value in achieving RVR of HCV-RNA load and IP10 after 48 hours of standard anti HCV therapy. METHODS HCV mono-infected and HIV/HCV co-infected patients naives to interferon were included. Demographic data, immune-virological HIV-related condition and HCV disease status were recorded before starting treatment. HCV-RNA and IP10 concentrations were also measured 48 hours after first interferon dose. Univariate model, logistic regression and ROC curve were performed for statistical analysis. RESULTS Thirty-two patients were enrolled (mean age 49.2 ± 5.6 years): all were treated with pegylated-interferon and ribavirin. Nineteen (59.3%) were HIV/HCV co-infected patients. RVR was reached in 10 patients (31.2%). A decline of more than two log of HCV-RNA after 48 hours of therapy was associated with RVR (P=0.004). A trend was observed between increased IP10 levels at 48 hours and RVR (P=0.08). In a multivariable model only HCV-RNA at 48 hours was associated with RVR (P=0.011). ROC curve analysis for both HCV-RNA at 48 hours and IP-10 at 48 hours showed an area under the curve of 0.87 (95%CI: 0.74-1; P=0.001) with specificity of 72.2% and sensibility of 90%. CONCLUSION In HCV treatment-naïve patients HCV-RNA and IP10 determination after 48 hours of interferon and ribavirin may be a worthwhile endpoint to predict RVR and select patients that may not require DAA addition.
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Affiliation(s)
- Roberta Prinapori
- Infectious Disease Clinic, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, 16132 Genova, Italy.
| | - Laura Sticchi
- Hygiene Unit, IRCCS AOU San Martino-IST, Genoa, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
| | | | - Filippo Del Puente
- Infectious Disease Clinic, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, 16132 Genova, Italy
| | - Giovanni Mazzarello
- Infectious Disease Clinic, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, 16132 Genova, Italy
| | - Anna Alessandrini
- Infectious Disease Clinic, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, 16132 Genova, Italy
| | - Alessio Signori
- Biostatistic Unit, Department of Health Sciences, Genoa, Italy
| | - Giancarlo Icardi
- Hygiene Unit, IRCCS AOU San Martino-IST, Genoa, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
| | | | - Claudio Viscoli
- Infectious Disease Clinic, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, 16132 Genova, Italy
| | - Antonio Di Biagio
- Infectious Disease Clinic, IRCCS Azienda Ospedaliera Universitaria San Martino - IST, 16132 Genova, Italy
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Cornberg M, Wiegand SB. ImPortance of IP-10 in hepatitis B. Antivir Ther 2015; 21:93-6. [PMID: 26598599 DOI: 10.3851/imp3014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2015] [Indexed: 10/22/2022]
Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
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Johansson S, Talloen W, Tuefferd M, Darling JM, Scholliers A, Fanning G, Fried MW, Aerssens J. Plasma levels of growth-related oncogene (CXCL1-3) associated with fibrosis and platelet counts in HCV-infected patients. Aliment Pharmacol Ther 2015; 42:1111-21. [PMID: 26314558 PMCID: PMC4592471 DOI: 10.1111/apt.13389] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 02/12/2015] [Accepted: 08/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Fibrosis progression in hepatitis C virus (HCV)-infected patients varies greatly between individuals. Chemokines recruit immune cells to the infected liver and may thus play a role in the fibrosis process. AIM To investigate plasma levels of a diverse chemokine panel in relation to liver fibrosis. METHODS African-American and Caucasian HCV genotype 1 infected patients were treated with peginterferon (pegIFN) and ribavirin (RBV) for 48 weeks (VIRAHEP-C cohort). Plasma levels of 13 cytokines were studied at baseline (n = 386). Subsequently, GROα levels were assessed in a sub cohort (n = 99) at baseline, and at 4 and 12 weeks after start of pegIFN/RBV treatment. RESULTS Increased severity of fibrosis (Ishak fibrosis score 0-2 vs. 3-6) was associated with increased plasma IP-10 (CXCL10) and IL-8 (CXCL8) levels, and decreased plasma levels of the chemokine growth-related oncogene (GRO, CXCL1-3). Plasma GRO levels were also positively correlated with platelet counts, and were higher in African-American as compared to Caucasian patients. In response to pegIFN/RBV treatment, GROα levels increased in Caucasian but not African-American patients from week 4 onwards. CONCLUSIONS The association with severity of fibrosis and platelet count positions plasma GRO as a potential biomarker for liver fibrosis in HCV-infected patients. The secretion of GRO by platelets may explain the correlation between GRO plasma level and platelet count. The ethnic difference in GRO levels both pre-treatment and in response to pegIFN/RBV might be driven by a genetic polymorphism in GROα associated with higher plasma levels and more common in the African-American population.
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