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1.
Gastroenterology ; 143(6): 1576-1585.e4, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22929808

RESUMEN

BACKGROUND & AIMS: In patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, antiviral functions of T cells are impaired; these might be increased by blocking T-cell co-inhibitory pathways, such as preventing interaction between the receptor programmed death (PD)-1 and its ligand, PD-L1. We attempted to optimize the restoration of T-cell functions in patients with chronic HBV or HCV infection with a combination of reagents that block PD-1 interaction with PD-L1 and stimulate T-cell signaling via CD137, a member of the tumor necrosis factor-receptor family. METHODS: We assessed the effects of CD137 stimulation (via CD137L), alone or in combination with antibodies that block PD-1 interaction with PD-L1 (anti-PD-L1), on proliferation and production of interferon-γ and interleukin-2 by intrahepatic and peripheral T cells from patients with chronic HBV or HCV infection. We also analyzed expression of different co-stimulatory molecules on virus-specific CD8+ and forkhead box P3+CD4+ cells by flow cytometry. RESULTS: Incubation of intrahepatic T cells with CD137L and anti-PD-L1 increased their responses to HBV, but not HCV. However, HCV-specific T cells isolated from peripheral blood were sensitive to these reagents. Virus-specific T cells from some, but not all patients, had increased responses to anti-PD-L1 when CD137L was added because in some cases the combination of anti-PD-L1 and CD137L overstimulated T cells, leading to their inhibition. Intrahepatic HBV- and HCV-specific CD8+ T cells had different costimulatory profiles; liver cells from patients with chronic HBV infection had a higher proportion of forkhead box P3+ regulatory T cells, with higher levels of PD-1, compared with liver cells from patients with chronic HCV infection. CONCLUSIONS: A combination of reagents that prevent interaction between PD-1 and its ligand and activate CD137 signaling increase responses of intrahepatic HBV-specific T cells and circulating HCV-specific T cells. This strategy might be developed to increase T-cell responses to these viruses in patients with chronic hepatitis B or C, and tailoring the dose of CD137L administered will help optimize results.


Asunto(s)
Diferenciación Celular/fisiología , Hepacivirus/fisiología , Virus de la Hepatitis B/fisiología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/patología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Adulto , Anciano , Anticuerpos/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Hepatitis B Crónica/metabolismo , Hepatitis B Crónica/patología , Hepatitis C Crónica/metabolismo , Hepatitis C Crónica/patología , Humanos , Técnicas In Vitro , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Ligandos , Masculino , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo
2.
Am J Gastroenterol ; 108(7): 1112-22, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23732467

RESUMEN

OBJECTIVES: The occurrence of decompensation marks a crucial turning point in the course of cirrhosis. The purpose of this study was to assess the risk of mortality according to the clinical characteristics of first decompensation, considering also the impact of acute-on-chronic liver failure (AoCLF). METHODS: We conducted a prospective nationwide inception cohort study in Italy. Decompensation was defined by the presence of ascites, either overt or detected by ultrasonography (UD), gastroesophageal variceal bleeding (GEVB), and hepatic encephalopathy (HE). AoCLF was defined according to the Asian Pacific Association for the Study of the Liver criteria. Multivariable Cox proportional hazards regression was used to analyze the risk of failure (death or orthotopic liver transplantation (OLT)). RESULTS: A total of 490 consecutive cirrhotic patients (314 males, mean age 60.9±12.6 years) fulfilled the study criteria. AoCLF was identified in 59 patients (12.0%). Among the remaining 431 patients, ascites were found in 330 patients (76.6%): in 257 (77.8%) as overt ascites and in 73 (22.2%) as UD ascites. GEVB was observed in 77 patients (17.9%) and HE in 30 patients (7.0%). After a median follow-up of 33 months, 24 patients underwent OLT and 125 died. The cumulative incidence of failure (death or OLT) after 1, 2, and 3 years was, respectively, 28, 53, and 62% in patients with AoCLF; 10, 18, and 25% in patients with UD ascites; 17, 31, and 41% in patients with overt ascites; and 8, 12, and 24% in patients with GEVB (P<0.0001). CONCLUSIONS: AoCLF is responsible for a relevant proportion of first decompensation in cirrhotic patients and is associated with the poorest outcome. Patients with UD ascites do not have a negligible mortality rate and require clinical monitoring similar to that of patients with overt ascites.


Asunto(s)
Cirrosis Hepática/mortalidad , Fallo Hepático/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ascitis/etiología , Carcinoma Hepatocelular/etiología , Várices Esofágicas y Gástricas/tratamiento farmacológico , Várices Esofágicas y Gástricas/etiología , Femenino , Estudios de Seguimiento , Hemorragia Gastrointestinal/tratamiento farmacológico , Hemorragia Gastrointestinal/etiología , Encefalopatía Hepática/etiología , Humanos , Italia/epidemiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugía , Fallo Hepático/etiología , Fallo Hepático/cirugía , Neoplasias Hepáticas/etiología , Trasplante de Hígado/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Adulto Joven
3.
Alcohol Clin Exp Res ; 37(6): 891-5, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23298155

RESUMEN

BACKGROUND: Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self-reported drinking habits lack reliability. We hypothesized that carriage of high-repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge-drinking and risk-seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome. METHODS: A cohort of HCV patients with normal or near-normal aminotransferases (N = 128) underwent a liver biopsy as part of diagnostic work-up. None admitted to exceed low-risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow-up period of 10 years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N = 128) and related to liver histology. RESULTS: HRV allele frequencies were 0.19 in patients and 0.16 in controls (p = 0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p = 0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p = 0.002) and stage (p = 0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR = 1.06, 95% CI 1.02 to 1.11) and HRV (OR = 3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow-up. CONCLUSIONS: The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C.


Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Hepatitis C Crónica/patología , Cirrosis Hepática/patología , Receptores de Dopamina D4/genética , Autoinforme , Consumo de Bebidas Alcohólicas/patología , Consumo Excesivo de Bebidas Alcohólicas/genética , Biopsia , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Frecuencia de los Genes , Hepatitis C Crónica/complicaciones , Cirrosis Hepática/complicaciones , Estudios Longitudinales , Repeticiones de Minisatélite/genética , Análisis Multivariante , Factores de Riesgo , Asunción de Riesgos , Índice de Severidad de la Enfermedad
4.
J Med Virol ; 84(5): 747-55, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22431022

RESUMEN

The interleukin 28B (IL-28B) rs12979860 C/T polymorphism is a predictor of spontaneous and treatment-induced hepatitis C virus (HCV) clearance. The C/C genotype is associated with higher serum cholesterol, predictor of a favorable outcome in chronic hepatitis C. Whether IL-28B polymorphism and serum cholesterol play a role in modulating the history of mild hepatitis C is unknown. To clarify this issue, 93 untreated patients infected with HCV with normal or near-normal transaminases and an initial Ishak staging score ≤1 were investigated retrospectively in the longitudinal study (median histological follow-up of 10 years). An additional confirmatory cohort of 143 patients with chronic HCV infection and abnormal levels of transaminases was evaluated in the cross-sectional study. In the longitudinal study, at the end of follow-up, Ishak staging scores progressed more frequently among carriers of a T/* allele who had a baseline serum cholesterol ≤175 mg/dl than in remaining patients: 6/36 (change ≤0), 15/45 (change 1-2), 6/12 (change ≥3), improvement chi-square P < 0.02, OR 3.1, 95% C.I. 1.3-7.7. In the cross-sectional study, the frequency of patients carrying the T/T genotype or serum cholesterol values ≤175 mg/dl increased starting from those with a staging score ≤2 (36/76, 47.4%), to those with a staging score of 3-4 (26/41, 63.4%) and to those with a staging score of 5-6 (20/26, 76.9%, P < 0.01 for linear trend). In conclusion, the interaction between IL-28B rs12979860 T/T genotype and low serum cholesterol concentration is an independent predictor of a worse disease course among patients infected with HCV with normal or near-normal transaminases.


Asunto(s)
Colesterol/sangre , Progresión de la Enfermedad , Hepatitis C Crónica/patología , Interleucinas/genética , Cirrosis Hepática/patología , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Niño , Estudios Transversales , Femenino , Hepatitis C Crónica/virología , Humanos , Interferones , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Transaminasas/sangre , Adulto Joven
5.
J Gastroenterol Hepatol ; 26(2): 328-33, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21261723

RESUMEN

BACKGROUND AND AIM: Carriage of the apolipoprotein E (Apo E) variants, E2, E3 and E4, affects cholesterol metabolism and may be involved in the persistence of hepatitis C virus (HCV) infection. Our aim was to verify whether carriage of specific Apo E variants modulates the course of hepatitis C. METHODS: We studied a cohort of 116 HCV-positive patients (49 male subjects) with persistently normal transaminases and an Ishak staging score ≤ 2 at an initial biopsy. These untreated patients underwent regular clinical monitoring (median histological follow up: 10 years). Apo E variants were genotyped and results were related to the histological outcome. RESULTS: The mean ± standard deviation staging scores were 0.9 ± 0.7 at entry versus 1.9 ± 1.2 at the end of follow up, P < 0.0001. Initial and final staging scores in the E3/E3 homozygotes (n = 74) were 1.0 ± 0.7 versus 2.1 ± 1.3, P < 0.0001, while in the remaining patients (n = 42) they were 0.9 ± 0.6 versus 1.5 ± 1.0, P < 0.002. A synergistic effect was observed between Apo E polymorphisms and baseline serum cholesterol values: patients not carrying any E3 allele, as well as carriers of a single E3 allele with serum cholesterol concentration > 190 mg/dL were more likely to have a favorable outcome (final vs initial staging score increased in 7/66, did not change in 10/46, and decreased in 3/4, P <0.005). CONCLUSIONS: Some of the variability in the natural history of patients with persistently normal transaminases with initially mild hepatitis C can be related to their Apo E genetic background.


Asunto(s)
Alanina Transaminasa/sangre , Apolipoproteínas E/genética , Hepatitis C Crónica/genética , Cirrosis Hepática/genética , Polimorfismo Genético , Adolescente , Adulto , Biomarcadores/sangre , Biopsia , Índice de Masa Corporal , Distribución de Chi-Cuadrado , Niño , Colesterol/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Hepatitis C Crónica/enzimología , Hepatitis C Crónica/etnología , Humanos , Italia , Cirrosis Hepática/enzimología , Cirrosis Hepática/etnología , Cirrosis Hepática/virología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Población Blanca/genética , Adulto Joven
6.
Hepatology ; 49(5): 1460-8, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19353740

RESUMEN

UNLABELLED: The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-alpha2a (PEG IFN-alpha2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-alpha2a 180 microg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 microg/week PEG IFN-alpha2a. In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments induced a continuous decay in viral load that reached -4.61 +/- 1.88 and -4.75 +/- 2.19 log(10) IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by -5.91 +/- 1.11 and -5.89 +/- 0.43 log(10) IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-alpha2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). CONCLUSION: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-alpha2a.


Asunto(s)
Antivirales/uso terapéutico , Ciclosporina/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Carga Viral , Adulto , Anciano , Ciclosporina/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Adulto Joven
7.
Hum Immunol ; 71(10): 999-1004, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20655350

RESUMEN

Genetic polymorphisms of interleukin-6 (IL-6) (-1363G>T, -597G>A, -572G>C, -174G>C, +2954G>C) may affect the outcomes of several diseases. This study was aimed to verify the role of these polymorphisms on the disease progression of patients with hepatitis C virus (HCV) infection and persistently normal transaminases (PNALT). A total of 121 PNALT patients did not receive any antiviral treatment but underwent periodic clinical monitoring, including repeat biopsies, for a median of 120 months. IL6-1363G>T, -597G>A, -572G>C, -174G>C, +2954G>C polymorphisms were related to histologic fibrosis progression. Among patients whose grading and staging scores increased at the end of the follow-up ≥2 Ishak points (N = 60 and N = 26, respectively), IL-6 -174G>C genotype frequencies were GG 37/66, GC 21/45, CC 2/10 (p = 0.041) and GG 18/66, GC 8/45, CC 0/10 (p = 0.040), respectively. The following frequencies were observed for the 572G>C polymorphism: GG 50/105, GC 10/16, CC 0/0, and GG 19/105, GC 7/16, CC 0/0, respectively. Grading progression was independently associated with carriage of the G allele in -174G>C polymorphism (oddd ratio = 5.07%, 95% confidence interval = 0.959-26.8, p = 0.023). Staging progression was independently associated with carriage of the C allele in -572G>C polymorphism (odd ratio = 4.60%, 95% confidence interval 1.42-14.8, p = 0.012). IL-6 polymorphisms influence histologic progression of HCV in patients with PNALT.


Asunto(s)
Hepatitis C Crónica/genética , Hepatitis C Crónica/inmunología , Interleucina-6/genética , Adolescente , Adulto , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Hepatitis C Crónica/fisiopatología , Humanos , Cirrosis Hepática , Masculino , Persona de Mediana Edad , Polimorfismo Genético
8.
Am J Gastroenterol ; 99(5): 855-9, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15128350

RESUMEN

The risk of sexual transmission of hepatitis C virus (HCV) infection was evaluated among 895 monogamous heterosexual partners of HCV chronically infected individuals in a long-term prospective study, which provided a follow-up period of 8,060 person-years. Seven hundred and seventy-six (86.7%) spouses were followed for 10 yr, corresponding to 7,760 person-years of observation. One hundred and nineteen (13.3%) spouses (69 whose infected partners cleared the virus following treatment and 50 who ended their relationship or were lost at follow-up) contributed an additional 300 person-years. All couples denied practicing anal intercourse or sex during menstruation, as well as condom use. The average weekly rate of sexual intercourse was 1.8. Three HCV infections were observed during follow-up corresponding to an incidence rate of 0.37 per 1,000 person-years. However, the infecting HCV genotype in one spouse (2a) was different from that of the partner (1b), clearly excluding sexual transmission. The remaining two couples had concordant genotypes, but sequence analysis of the NS5b region of the HCV genome, coupled with phylogenetic analysis showed that the corresponding partners carried different viral isolates, again excluding the possibility of intraspousal transmission of HCV. Our data indicate that the risk of sexual transmission of HCV within heterosexual monogamous couples is extremely low or even null. No general recommendations for condom use seem required for individuals in monogamous partnerships with HCV-infected partners.


Asunto(s)
Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/transmisión , Heterosexualidad , Enfermedades Virales de Transmisión Sexual/epidemiología , Adulto , Distribución por Edad , Secuencia de Bases , Estudios de Cohortes , ADN Viral/análisis , Composición Familiar , Femenino , Hepatitis C Crónica/diagnóstico , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Prevalencia , Estudios Prospectivos , Medición de Riesgo , Distribución por Sexo , Enfermedades Virales de Transmisión Sexual/diagnóstico
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