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BACKGROUND & AIMS: Few studies have fully applied an enhanced recovery after surgery (ERAS) protocol to liver transplantation (LT). Our aim was to assess the effects of a comprehensive ERAS protocol in our cohort of low- and medium-risk LT patients. METHODS: The ERAS protocol included pre-, intra-, and post-operative steps. During the five-year study period, 181 LT were performed in our institution. Two cohorts were identified: low risk patients (n = 101) had a laboratory model for end-stage liver disease (MELD) score of 20 points or less at the time of LT, received a liver from a donor after brain death, and had a balance of risk score of 9 points or less; medium-risk patients (n = 15) had identical characteristics except for a higher MELD score (21-30 points). In addition, we analyzed the remaining patients (n = 65) who were transplanted over the same study period separately using the ERAS protocol. RESULTS: The low-risk cohort showed a low need for packed red blood cells transfusion (median: 0 units) and renal replacement therapy (1%), as well as a short length of stay both in the intensive care unit (13 h) and in the hospital (4 days); morbidity during one-year follow-up, and probability of surviving to one year (89.30%) and five years (76.99%) were in line with well-established reference data. Similar findings were observed in the medium-risk cohort. CONCLUSIONS: This single-center prospective observational cohort study provides evidence that ERAS is feasible and safe for low- and medium-risk LT.
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Recuperación Mejorada Después de la Cirugía , Trasplante de Hígado/efectos adversos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
AIM: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. MATERIAL AND METHODS: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. RESULTS: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. CONCLUSIONS: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.
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Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina , Anilidas/efectos adversos , Anilidas/uso terapéutico , Antivirales/efectos adversos , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , VIH-1/genética , Humanos , Lactamas Macrocíclicas , Modelos Logísticos , Compuestos Macrocíclicos/efectos adversos , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prolina/análogos & derivados , Ribavirina/efectos adversos , Ribavirina/uso terapéutico , España , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Respuesta Virológica Sostenida , Resultado del Tratamiento , Uracilo/efectos adversos , Uracilo/análogos & derivados , Uracilo/uso terapéutico , ValinaRESUMEN
Bacterial (bact)DNA is an immunogenic product that frequently translocates into the blood in cirrhosis. We evaluated bactDNA clearance in patients undergoing liver transplantation (LT) and its association with inflammation and clinically relevant complications. We prospectively included patients consecutively admitted for LT in a one-year follow-up study. We evaluated bactDNA before and during the first month after LT, quantifying cytokine response at 30 days. One hundred patients were included. BactDNA was present in the blood of twenty-six patients undergoing LT. Twenty-four of these showed bactDNA in the portal vein, matching peripheral blood-identified bactDNA in 18 cases. Thirty-four patients showed bactDNA in blood during the first month after LT. Median TNF-α and IL-6 levels one month after LT were significantly increased in patients with versus without bactDNA. Serum TNF-α at baseline was an independent risk factor for bactDNA translocation during the first month after LT in the multivariate analysis (Odds ratio (OR) 1.14 [1.04 to 1.29], P = 0.015). One-year readmission was independently associated with the presence of bactDNA during the first month after LT (Hazard ratio (HR) 2.75 [1.39 to 5.45], P = 0.004). The presence of bactDNA in the blood of LT recipients was not shown to have any impact on complications such as death, graft rejection, bacterial or CMV infections. The rate of bactDNA translocation persists during the first month after LT and contributes to sustained inflammation. This is associated with an increased rate of readmissions in the one-year clinical outcome after LT.
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Traslocación Bacteriana/fisiología , ADN Bacteriano/sangre , Interleucina-6/sangre , Trasplante de Hígado , Factor de Necrosis Tumoral alfa/sangre , Disbiosis/microbiología , Femenino , Microbioma Gastrointestinal/fisiología , Tracto Gastrointestinal/microbiología , Humanos , Inflamación/microbiología , Cirrosis Hepática/patología , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana Edad , Vena Porta/microbiología , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: The use of non-selective beta-blockers has been associated with lower rates of infection and reduced infection-associated morbidity in patients with cirrhosis. However, it is unknown if these drugs modify the systemic inflammatory response to circulating bacterial DNA. METHODS: Sixty-three patients with cirrhosis were included during an episode of decompensation by ascites. Thirty of those patients were on beta-blockers. Blood samples were obtained after each patient had been in the supine position for at least 30 minutes in a quiet atmosphere. Bacterial DNA, serum cytokines, nitric oxide, and LPS were determined. Phagocytic and oxidative burst activities were determined in polymorphonuclear cells from the patients. RESULTS: The detection rate of bacterial DNA in the blood was the same (33%) for patients not treated and treated with non-selective beta-blockers. Patients naive to non-selective beta-blockers showed significantly higher serum levels of IL6, IFN-gamma and IL10 in response to the presence of bacterial DNA. Patients treated with non-selective beta-blockers showed higher basal inflammatory activity that did not change with the presence of bacterial DNA. Monocytes and granulocytes from patients treated with non-selective beta-blockers showed a significantly increased phagocytic capacity in the presence of bacterial DNA. CONCLUSIONS: In patients with cirrhosis, chronic treatment with beta-blockers is associated with a higher unstimulated production of serum cytokines and an increased phagocytic activity in the presence of bacterial DNA.
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Antagonistas Adrenérgicos beta/uso terapéutico , ADN Bacteriano/sangre , Hipertensión Portal/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Cirrosis Hepática/fisiopatología , Estallido Respiratorio/efectos de los fármacos , Antagonistas Adrenérgicos beta/efectos adversos , Anciano , Ascitis/microbiología , Líquido Ascítico/microbiología , Traslocación Bacteriana/efectos de los fármacos , Citocinas/sangre , Femenino , Humanos , Hipertensión Portal/complicaciones , Modelos Lineales , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Análisis Multivariante , Neutrófilos/efectos de los fármacos , Óxido Nítrico/sangre , Estudios ProspectivosRESUMEN
INTRODUCTION: Patients with cirrhosis by hepatitis C virus infection treated with ß-blockers (BB) have been shown to have a reduced incidence of hepatocellular carcinoma (HCC). Also, an association between propranolol therapy and lower incidence of other tumors has been described. AIM: To analyze the incidence of HCC according to BB treatment in cirrhosis of any cause. PATIENTS AND METHODS: Cirrhotic patients included in the program for early detection of HCC were followed. Patients' data were prospectively registered, including transplantation and death. Patients were classified as chronically taken or not BB and the proportions of patients who remained free of tumor from the diagnosis of cirrhosis until the end of follow-up were compared using Kaplan-Meier analysis and the Breslow test. RESULTS: A total of 173 patients (73 treated and 100 untreated BB) were followed. The median duration of follow-up was 11 years. There were no differences between both groups in the overall survival, number of deaths, or liver transplant.Overall, 28 patients developed HCC during the follow-up, 20 patients who were untreated and eight patients treated with BB. The cumulative proportion of cases of HCC between untreated and treated with BB from the diagnosis of cirrhosis was statistically significant (6 vs. 3%, at 5 years; 19 vs. 6% at 10 years; 24 vs. 16% at 15 years; P=0.048). Multivariate analyses showed BB intake as the only significant variable associated with the development of HCC. CONCLUSION: Cirrhotic patients treated with BB have a lower cumulative probability of developing HCC during the 10 years after the diagnosis of cirrhosis.
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Antagonistas Adrenérgicos beta/uso terapéutico , Carcinoma Hepatocelular/prevención & control , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/prevención & control , Anciano , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/virología , Distribución de Chi-Cuadrado , Femenino , Hepatitis C/epidemiología , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/virología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Factores Protectores , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , España/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Hepatitis C virus infection remains prevalent among patients undergoing long-term haemodialysis and has a detrimental impact on survival in this population. Antiviral therapy for chronic hepatitis C in haemodialysis patients is still a challenge to clinicians. The aim of the current study is to evaluate the efficacy and safety of therapy with pegylated interferon, alone or combined with ribavirin, for chronic hepatitis C among patients undergoing long-term hemodialysis. METHODS: We conducted a retrospective, multicenter cohort trial with monotherapy (pegylated interferon) (n=21) or combined antiviral therapy (pegylated interferon plus ribavirin) (n=5) for chronic hepatitis C in patients undergoing long-term haemodialysis. RESULTS: Sustained virological response was obtained in eleven (42%) patients. Seven (26.9%) patients interrupted prematurely the antiviral treatment due to serious side-effects, the most frequent cause of treatment withdrawal being hematological (n=3). HCV RNA load was lower in responder than non-responder patients, 5.44 (3.45; 6.36) vs. 5.86 (4.61; 6.46) log10 copies/mL, even if the difference was not significant (P=0.099). Blood transfusion requirement was greater in patients on combined antiviral therapy than those on pegylated interferon alone, 100% (5/5) vs. 0% (0/21), P=0.0001. No difference in sustained viral response occurred between patients on combined antiviral therapy and those on pegylated interferon monotherapy [40% (2/5) vs. 42.8% (9/21), P=0.90]. CONCLUSIONS: Results from this study showed that pegylated interferon alone or with ribavirin is unsatisfactory in terms of efficacy and safety. Prospective trials based on interferon-free regimens (i.e., sofosbuvir plus ribavirin or sofosbuvir plus daclatasvir) are under way in patients with hepatitis C receiving long-term hemodialysis.
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Antivirales/administración & dosificación , Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Diálisis Renal , Ribavirina/administración & dosificación , Ribavirina/uso terapéutico , Adulto , Anciano , Antivirales/efectos adversos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hepatitis C Crónica/complicaciones , Humanos , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Estudios Prospectivos , ARN Viral/sangre , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Ribavirina/efectos adversos , Resultado del TratamientoRESUMEN
Use of non-steroidal anti-inflammatory drugs in cirrhosis has been associated with impairment of renal function based on its ability to inhibit the renal production of prostaglandins. Renal effects of dipyrone in patients with cirrhosis have not been evaluated. We aimed to assess the renal effect of therapeutic doses of dipyrone used for short periods of time in patients with cirrhosis. Twenty-nine patients with cirrhosis were included in an observer-blind clinical trial. Patients were randomized to receive three times a day oral acetaminophen (500 mg; N = 15) or dipyrone (575 mg; N = 14) for 72 hr. Serum and urine samples were obtained at baseline, 48 and 72 hr, and cystatin C, creatinine, aldosterone, 6-keto-Prostaglandin-F1 alpha and prostaglandin E2 were measured. Cystatin C and creatinine levels remained comparable in patients treated with acetaminophen and dipyrone. Urine and serum prostaglandins concentrations were significantly decreased at 72 hr in patients treated with dipyrone regardless of the status of ascites. One patient with ascites treated with dipyrone required a paracentesis and developed renal insufficiency. We conclude that dipyrone and acetaminophen did not reduce renal function when used for short periods of time (up to 72 hr) in patients with cirrhosis. However, considering that dipyrone lowered renal vasodilator prostaglandins synthesis, acetaminophen appears as the safest choice with respect to kidney function in cirrhosis.
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Dipirona/efectos adversos , Riñón/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Prostaglandinas/metabolismo , Acetaminofén/administración & dosificación , Acetaminofén/efectos adversos , Acetaminofén/uso terapéutico , Adulto , Anciano , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/uso terapéutico , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Ascitis/tratamiento farmacológico , Dipirona/administración & dosificación , Dipirona/uso terapéutico , Femenino , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Método Simple Ciego , Factores de TiempoRESUMEN
BACKGROUND AND AIM: Prophylactic treatment of variceal bleeding in cirrhotic patients with beta-blockers is effective in only some patients. Our aim was to determine whether the response of the hepatic venous pressure gradient (HVPG) to the intravenous administration of propranolol predicts the response after chronic oral propranolol treatment. PATIENTS AND METHODS: We included prospectively cirrhotic patients with esophageal varices under primary prophylaxis (PP) and secondary prophylaxis (SP). The HVPG was measured at baseline and after a propranolol bolus (0.15 mg/kg intravenous). A patient was considered a good-responder if HVPG decreased to 12 mmHg or 20% from baseline. Patients then received oral propranolol (heart rate titrated). Poor-responders under SP were also included in a variceal band ligation program. After at least 3 months, a second hemodynamic study was conducted. RESULTS: Fifty-six patients were included (36 SP and 20 PP). Response rate was similar (32.1 and 41.9%, P=0.7) and the Pearson's correlation coefficient was 0.61 (P=0.001). In 81.4% patients, the first study predicted the response status of the second. Six patients rebled on follow-up between the studies, all of them were poor responders to intravenous propranolol. CONCLUSION: A single hemodynamic study using intravenous propranolol seems to predict chronic response to propranolol.
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Antagonistas Adrenérgicos beta/administración & dosificación , Várices Esofágicas y Gástricas/tratamiento farmacológico , Várices Esofágicas y Gástricas/etiología , Cirrosis Hepática/complicaciones , Propranolol/administración & dosificación , Administración Oral , Várices Esofágicas y Gástricas/prevención & control , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Proyectos Piloto , Valor Predictivo de las Pruebas , Estudios Prospectivos , Resultado del Tratamiento , Presión Venosa/efectos de los fármacosRESUMEN
Hepatitis C virus (HCV) presents several regions involved potentially in evading antiviral treatment and host immune system. Two regions, known as PKR-BD and V3 domains, have been proposed to be involved in resistance to interferon. Additionally, hypervariable regions in the envelope E2 glycoprotein are also good candidates to participate in evasion from the immune system. In this study, we have used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples obtained just before initiation of therapy and after 6 or/and 12 months of treatment were available. A range of 25-100 clones per patient, genome region and time sample were obtained. The predominant amino acid sequences for each time sample and patient were determined. Next, the sequences of the PKR-BD and V3 domains and the hypervariable regions from different time samples were compared for each patient. The highest levels of variability were detected at the three hypervariable regions of the E2 protein and, to a lower extent, at the V3 domain of the NS5A protein. However, no clear patterns of adaptation to the host immune system or to antiviral treatment were detected. In summary, although high levels of variability are correlated to viral adaptive response, antiviral treatment does not seem to promote convergent adaptive changes. Consequently, other regions must be involved in evasion strategies likely based on a combination of multiple mechanisms, in which pools of changes along the HCV genome could confer viruses the ability to overcome strong selective pressures.
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Antivirales , Farmacorresistencia Viral , Hepacivirus , Hepatitis C/tratamiento farmacológico , Interferón-alfa , Mutación , Ribavirina , Secuencia de Aminoácidos , Antivirales/farmacología , Antivirales/uso terapéutico , Quimioterapia Combinada , Hepacivirus/química , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/virología , Humanos , Interferón alfa-2 , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Datos de Secuencia Molecular , Proteínas Recombinantes , Ribavirina/farmacología , Ribavirina/uso terapéutico , Insuficiencia del Tratamiento , Proteínas del Envoltorio Viral/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
UNLABELLED: We tested the hypothesis that the presence of bacterial DNA (bactDNA) in ascitic fluid and serum is associated with decreased survival in patients with cirrhosis. In a prospective, multicenter study, we analyzed the clinical evolution of 156 patients with cirrhosis and ascites (first or recurrence) with lower than 250 polymorphonuclear cells (PMN)/muL, negative ascites bacteriological culture, and absence of other bacterial infections being admitted for evaluation of large-volume paracentesis, according to the presence of bactDNA at admission. Survival, causes of death, and successive hospital admissions were determined during a 12-month follow-up period. BactDNA was detected in 48 patients. The most prevalent identified bactDNA corresponded to Escherichia coli (n = 32/48 patients, 66.6%). Patients were followed for 12 months after inclusion and in this period 34 patients died: 16 of 108 (15%) bactDNA negative versus 18 of 48 (38%) bactDNA positive (P = 0.003). The most frequent cause of death was acute-on-chronic liver failure in both groups (7/16 and 9/18 in patients without or with bactDNA, respectively), although more prevalent in the first month of follow-up in patients with presence of bactDNA (0 versus 4/7). When considering patients with model for end-stage liver disease (MELD) score less than 15, mortality was significantly higher in those with presence of bactDNA. Spontaneous bacterial peritonitis developed similarly in patients with or without bactDNA at admission. CONCLUSION: The presence of bactDNA in a patient with cirrhosis during an ascitic episode is an indicator of poor prognosis. This fact may be related to the development of acute-on-chronic liver failure at short term and does not predict the development of spontaneous bacterial peritonitis.
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Líquido Ascítico/microbiología , ADN Bacteriano/sangre , Cirrosis Hepática/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Ascitis/epidemiología , Ascitis/microbiología , Escherichia coli/genética , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Estimación de Kaplan-Meier , Cirrosis Hepática/metabolismo , Cirrosis Hepática/mortalidad , Fallo Hepático/epidemiología , Fallo Hepático/microbiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neutrófilos/microbiología , Peritonitis/epidemiología , Peritonitis/microbiología , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures.
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Antivirales/uso terapéutico , Variación Genética , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Ribavirina/uso terapéutico , Regiones Determinantes de Complementariedad/efectos de los fármacos , Evolución Molecular , Variación Genética/efectos de los fármacos , Genoma Viral/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Interferón alfa-2 , Filogenia , Proteínas Recombinantes , Proteínas no Estructurales Virales/efectos de los fármacos , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND/AIMS: Surveillance programmes (SPs) for hepatocellular carcinoma (HCC) in patients with cirrhosis intend to diagnose the tumour in its early stages when an effective therapy can be applied. The aims of this study have been to compare the survival of patients with HCC being diagnosed or not in SPs, and to establish a more accurate profile of the best target population. METHODS: From January 1996 to June 2005, 290 patients with HCC were included. The relationship between being diagnosed or not in an SP and survival has been analysed in a univariate analysis. Pretreatment variables found to be significant predictors of survival in univariate analysis were included in a multivariate analysis. RESULTS: The mean survival for patients diagnosed in SPs (27 months, 16.6-37.4) was significantly longer than in patients being diagnosed out of these programmes (6 months, 2.6-9.4) (P=0.001). Child-Pugh class A [beta 1.4, 95% confidence interval (CI) 1.14-1.78; P=0.0002] and being diagnosed in SPs (beta 0.4, 95% CI 0.3-0.6; P=0.0003) became the only independent predictive factors of longer survival. CONCLUSIONS: SPs for HCC allow the detection of small tumours and the application of intention-to-cure therapies, which improves survival. However, these programmes do not improve prognosis in patients with advanced cirrhosis.
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Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Vigilancia de la Población , Anciano , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
We have conducted a large sequence study of the E1-E2 and NS5A regions of the HCV, subtypes 1a and b, both in patients previously treated with interferon, and untreated patients, who later responded, or not, to a combination therapy based on interferon plus ribavirin. We have examined the role played by the number of positively selected sites on disease progression and its relationship with several variables such as patients' age, sex and their risk of acquiring the disease. We have detected three groups of patients that respond or not to combination therapy: responders of intermediate age, older non-responders and young non-responders, they possess an increasing average number of positively selected sites in the E1-E2 region, respectively. We conclude that the host's genetic factors play an important role in whether the disease is contained or becomes chronic.
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Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Interferones/uso terapéutico , Ribavirina/uso terapéutico , Selección Genética , Adulto , Anciano , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , ARN Viral/genética , Análisis de Secuencia de ADN , Resultado del Tratamiento , Proteínas del Envoltorio Viral/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
The degree of variability of the interferon sensitivity determining region (ISDR) in the hepatitis C virus (HCV) genome has been postulated to predict the response to interferon therapy, mainly in patients infected with subtype 1b, although this prediction has been the subject of a long controversy. This prediction has been tested by analyzing a cohort of 67 Spanish patients infected with HCV genotype 1, 23 of which were infected with subtype 1a and 44 with subtype 1b. A sample previous to therapy with alpha-interferon plus ribavirin was obtained and several clones (between 25 and 96) including the ISDR were sequenced from each patient. A significant correlation between mutations at the ISDR and response to treatment for subtype 1b patients, but not for those infected with subtype 1a, has been detected. Although the results suggest that the same relationship holds true for subtype 1a, lack of statistical power because of the small sample size of this subtype prevented firmer conclusions. However, identical ISDR sequences were found in responder and non-responder patients, suggesting that the stability of the ISDR sequence can occasionally help HCV to evade interferon therapy, although this is not a sufficient condition. More complex interactions, including the ISDR or not, are likely to exist and govern the HCV response to interferon treatment.
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Antivirales/farmacología , Farmacorresistencia Viral/genética , Hepacivirus/inmunología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Interferones/farmacología , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Antivirales/uso terapéutico , Genoma Viral/genética , Hepacivirus/genética , Humanos , Interferones/uso terapéutico , Datos de Secuencia Molecular , Mutación , Ribavirina/uso terapéutico , Análisis de Secuencia de ADN , EspañaRESUMEN
The envelope 2 protein of hepatitis C virus (HCV) presents three hypervariable regions, named HVR1, HVR2 and HVR3, in which the presence of antigenic sites has been described. Genetic variability in these regions may reflect the generation of escape mutants as a consequence of the immune response. Therefore, these regions would tend to accumulate amino acid changes along the infection process, an effect that could be accelerated by antiviral treatments. In this study, we have analyzed the E1-E2 region of 23 HCV patients non-responders to antiviral treatment, 7 of which were infected with subtype 1a, 15 with subtype 1b, and 1 with a new HCV-1 subtype, before and after 6 and/or 12 months of peg-interferon+ribavirin treatment. We have sequenced about 100 clones from each sample, analyzing a total of 4906 sequences. A detailed analysis of the evolutionary forces acting along the genome region studied confirmed the existence of the three hypervariable regions, characterized by significant changes in amino acid composition between samples taken at different times from the same patient and a high number of sites evolving under positive selection. Moreover, for the recently described HVR3, our results suggest that its location could be restricted to residues 434-450, instead of the originally postulated 431-466.
Asunto(s)
Evolución Biológica , Regiones Determinantes de Complementariedad/genética , Hepacivirus/genética , Proteínas del Envoltorio Viral/genética , Secuencia de Aminoácidos , Antivirales/farmacología , Variación Genética , Hepacivirus/efectos de los fármacos , Humanos , Datos de Secuencia Molecular , ARN Viral/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: The extended treatment with lamivudine in patients with chronic hepatitis B is associated with the emergence of resistances. Patients with resistance to lamivudine show a loss of biochemical and virological responses and a higher progression of their liver disease. Adefovir dipivoxil, an analogue of the nucleotides, is effective for the treatment of patients with resistance to lamivudine. The aim of this study was to evaluate the efficacy, safety and resistance of adefovir dipivoxil in patients with chronic hepatitis B refractory to treatment with lamivudine. PATIENTS AND METHOD: One hundred and twenty hepatits B virus patients refractory to lamivudine were treated with adefovir dipivoxil. Seventy-four patients were followed up during two years. In all cases, the hepatitis B virus-DNA was determined by polymerase chain reaction, and in those cases without response to treatment, the presence of resistances to adefovir and lavimudine were studied. RESULTS: At the second year of treatment, we observed a biological response of 54.1%, a biochemical response of 62.2%, while an elimination of hepatitis B e antigen was seen in 21% cases. 20% patients developed resistance to adefovir dipivoxil, and the most frequent detected mutations were: A181V, A181T and N236T. Drug safety was excellent; in fact, only one adverse effect related to the drug was detected. CONCLUSIONS: Treatment with adefovir dipivoxil for 2 years in mono-therapy in patient who are previously non-responders to lavimudine is associated with a high biochemical and virologycal response with an excellent safety. At the second year of treatment, the adefovir dipivoxil resistance rate is 20%.
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Adenina/uso terapéutico , Adolescente , Adulto , Anciano , Farmacorresistencia Viral , Femenino , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , EspañaRESUMEN
Little is known about the potential effects of insertions and deletions (indels) on the evolutionary dynamics of hepatitis C virus (HCV). In fact, the consequences of indels on antiviral treatment response are a field of investigation completely unexplored. Here, an extensive sequencing project was undertaken by cloning and sequencing serum samples from 25 patients infected with HCV subtype 1a and 48 patients with subtype 1b. For 23 patients, samples obtained after treatment with alpha interferon plus ribavirin were also available. Two genome fragments containing the hypervariable regions in the envelope 2 glycoprotein and the PKR-BD domain in NS5A were sequenced, yielding almost 16 000 sequences. Our results show that insertions are quite rare, but they are often present in biologically relevant domains of the HCV genome. Moreover, their frequency distributions between different time samples reflect the quasispecies dynamics of HCV populations. Deletions seem to be subject to negative selection.
Asunto(s)
Hepacivirus/genética , Hepatitis C/virología , Secuencia de Aminoácidos , Antivirales/uso terapéutico , Quimioterapia Combinada , Eliminación de Gen , Genes Virales/genética , Hepatitis C/clasificación , Hepatitis C/tratamiento farmacológico , Humanos , Interferón-alfa/uso terapéutico , Datos de Secuencia Molecular , Mutagénesis Insercional , Ribavirina/uso terapéutico , Alineación de Secuencia , España , Especificidad de la Especie , Proteínas del Envoltorio Viral/genética , Proteínas no Estructurales Virales/genéticaRESUMEN
Hepatitis C virus (HCV) infection affects about 3% of the human population. Phylogenetic analyses have grouped its variants into six major genotypes, which have a star-like distribution and several minor subtypes. The most abundant genotype in Europe is the so-called genotype 1, with two prevalent subtypes, 1a and 1b. In order to explain the higher prevalence of subtype 1b over 1a, a large-scale sequence analysis (100 virus clones) has been carried out over 25 patients of both subtypes in two regions of the HCV genome: one comprising hypervariable region 1 and another including the interferon sensitivity-determining region. Neither polymorphism analysis nor molecular variance analysis (attending to intra- and intersubtype differences, age, sex and previous history of antiviral treatment) was able to show any particular difference between subtypes that might account for their different prevalence. Only the demographic history of the populations carrying both subtypes and analysis of molecular variance (AMOVA) for risk practice suggested that the route of transmission may be the most important factor to explain the observed difference.
Asunto(s)
Hepacivirus/clasificación , Hepatitis C Crónica/epidemiología , Análisis de Varianza , Variación Genética , Hepacivirus/genética , Hepacivirus/fisiología , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Datos de Secuencia MolecularRESUMEN
PURPOSE: Some new staging systems in hepatocellular carcinoma (HCC) have been described in the last years. The aim of this study was to compare the survival-predicting capacity of some variables and the prognostic classifications. METHODS: Demographic, clinical, analytical variables and tumour characteristics were collected in a study including 115 patients with HCC. Predictors of survival were identified using the Kaplan-Meier test and the Cox model. Comparison between different staging systems was carried out. RESULTS: The 1-, 2- and 3-year estimated survival was 65%, 45% and 30%, respectively. Child-Pugh score and alpha-fetoprotein level greater than 400 UI/l were independent predictors of survival in the Cox model. Although all systems correctly differentiated between patients regarding survival (Kaplan-Meier, log rank < 0.05 for all), the Barcelona Clinic Liver Cancer (BCLC) showed a better discriminatory ability than the other evaluated scores. In addition, the independent homogenizing ability and stratification value of BCLC was better than that of other systems. On the contrary, model for end-stage liver disease (MELD) showed the worst results. CONCLUSIONS: Child-Pugh score and alpha-fetoprotein levels were the only independent predictors of survival in patients with HCC. Child-Pugh score showed a better prediction value for survival when compared with MELD. BCLC is more accurate than the other prognostic models evaluated in this investigation.