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2.
Liver Int ; 35(1): 90-100, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25113158

ABSTRACT

BACKGROUND & AIMS: The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection. METHODS: Prospective, multicentre, national registry that includes naïve and treatment-experienced patients with HCV genotype 1 infection, who had bridging fibrosis or cirrhosis and were treated with triple therapy (peginterferon alfa-2a or alfa-2b, ribavirin and boceprevir) as compassionate use, and in accordance with the Summary of Product Characteristics. RESULTS: Most of the patients (68.2%) were male, with a mean age of 53 years, 75% (n = 128) had HCV 1b genotype and baseline viral load of 6.2 log. According to prior treatment, 20% of patients were treatment-naïve and 80% had received prior treatment. Approximately 36.5% of patients (n = 62) reported at least one serious adverse events (SAEs) (total SAEs = 103). The most common SAEs were neutropenia (57.6%), anaemia (47.6%) and grade 3 thrombopenia (25.9%). Patients with albumin <3.5 g/dl and bilirubin >2 mg/dl had an increased relative risk (greater than one-fold) for SAEs, including infections and hepatic decompensation. In the intent-to-treat analysis (n = 170), the overall percentage of patients with SVRw12 was 46.5%. In patients with 1 log decrease at week 4 (lead-in phase), the overall SVRw12 rate was 67.0%. In the patients initiating triple therapy with boceprevir (n = 139), the global response rate was 56.4%. In a multivariate analysis, an increased probability of achieving SVR was associated with response to prior treatment (relapsers), >1 log decrease in viral load in the lead-in phase and baseline albumin >3.5 g/dl. CONCLUSIONS: Triple therapy in patients with severe fibrosis/cirrhosis is associated with a higher rate of SAE and a lower rate in comparison with patients with mild disease. However, for patients with intact liver function, it could be considered as a treatment option, when other alternatives would not be available.


Subject(s)
Hepacivirus/genetics , Hepatitis C/drug therapy , Interferon-alpha/therapeutic use , Liver Cirrhosis/drug therapy , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , Protease Inhibitors/therapeutic use , Ribavirin/therapeutic use , Compassionate Use Trials , Drug Therapy, Combination/adverse effects , Hepatitis C/complications , Hepatitis C/genetics , Humans , Interferon-alpha/adverse effects , Liver Cirrhosis/etiology , Male , Middle Aged , Polyethylene Glycols/adverse effects , Proline/adverse effects , Proline/therapeutic use , Prospective Studies , Protease Inhibitors/adverse effects , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Ribavirin/adverse effects , Spain
3.
Cell Immunol ; 269(2): 104-14, 2011.
Article in English | MEDLINE | ID: mdl-21481848

ABSTRACT

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity.


Subject(s)
Antigens, CD/metabolism , Apoptosis Regulatory Proteins/metabolism , Apoptosis/immunology , Hepatitis C, Chronic/immunology , Interleukin-7 Receptor alpha Subunit/metabolism , Membrane Proteins/metabolism , Proto-Oncogene Proteins/metabolism , T-Lymphocytes, Cytotoxic/immunology , Adult , Amino Acid Chloromethyl Ketones/pharmacology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Apoptosis/drug effects , B7-H1 Antigen , Bcl-2-Like Protein 11 , Cell Count , Cell Proliferation/drug effects , Female , Humans , Immunophenotyping , Liver/immunology , Liver/pathology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Count , Male , Middle Aged , Programmed Cell Death 1 Receptor , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/physiology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Viral Load/immunology , Viral Nonstructural Proteins/immunology
4.
World J Gastroenterol ; 14(47): 7149-59, 2008 Dec 21.
Article in English | MEDLINE | ID: mdl-19084927

ABSTRACT

Chemokines produced in the liver during hepatitis C virus (HCV) infection induce migration of activated T cells from the periphery to infected parenchyma. The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell (Th1/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1 alpha; MIP-1 alpha), CCL4 (MIP-1 beta), CCL5 (regulated on activation normal T cell expressed and secreted; RANTES), CXCL10 (interferon-gamma-inducible protein-10; IP-10), CXCL11 (interferon-inducible T-cell alpha chemoattractant; I-TAC), and CXCL9 (monokine induced by interferon gamma; Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors. Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C. The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. When the adaptive immune response fails in this task, non-specific T cells without the capacity to control the infection are also recruited to the liver, and these are ultimately responsible for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.


Subject(s)
Chemokines/physiology , Hepatitis C, Chronic/physiopathology , Liver/virology , Receptors, Chemokine/physiology , Animals , Antiviral Agents/therapeutic use , Disease Models, Animal , Hepacivirus/pathogenicity , Hepatitis C, Chronic/drug therapy , Humans , Liver/physiopathology , Treatment Outcome
5.
Arch Pathol Lab Med ; 130(8): 1188-92, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16879021

ABSTRACT

CONTEXT: Mast cells (MCs) have been implicated in fibrogenesis, angiogenesis, and immunity against bacteria. These 3 mechanisms participate in the peritoneal pathology secondary to peritoneal dialysis (PD) treatment. Despite their potential relevance to PD-related pathology, few studies have focused on MCs. OBJECTIVE: To evaluate possible variations in the number of MCs during PD treatment. DESIGN: A quantitative study of tissue MCs in normal and pathologic peritoneum. Parietal peritoneal biopsies were collected from 4 groups: (1) normal controls (n = 9), (2) uremic non-PD patients (n = 16), (3) uremic patients on PD (n = 26), and (4) non-renal patients with inguinal hernia (n = 20). MCs were evaluated using immunohistochemistry for the detection of tryptase. The total number of cross sections of vessels per peritoneal field was examined in 22 of the 26 peritoneal biopsies of PD patients. RESULTS: PD tissue samples showed fibrosis, mesothelial cell loss, and variable hyalinizing vasculopathy. The number of MCs was similar in normal controls and non-PD uremic patients (mean +/- SE: 7.13 +/- 0.67 and 7.74 +/- 0.74 MCs/mm2, respectively). Peritoneal dialysis patients showed a reduction (4 +/- 0.38 MCs/mm2, P < .001), whereas hernia sac samples showed an increase (10.59 +/- 3.48 MCs/mm2). MC reduction showed no correlation with time on dialysis, fibrosis, number of vessels, or previous episodes of peritonitis. CONCLUSIONS: The peritoneum of patients receiving PD treatment shows a reduction of MCs. Despite such a reduction, fibrosis takes place, suggesting that MCs do not play a critical role in fibrosis genesis. Mast cell loss may be a contributory factor to peritonitis episodes in PD patients.


Subject(s)
Cell Count/methods , Mast Cells/pathology , Peritoneal Dialysis , Peritoneum/cytology , Peritoneum/pathology , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , Female , Fibrosis/pathology , Hernia/blood , Humans , Immunohistochemistry , Male , Middle Aged , Peritoneum/metabolism , Uremia/blood , Uremia/therapy
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