RESUMEN
Background: To analyze key indicators of metabolic control in adults with type 1 diabetes (T1D) using real-time or intermittent scanning continuous glucose monitoring (rtCGM/iscCGM) during real-life care, based on the German/Austrian/Swiss Prospective Diabetes Follow-up (DPV) registry. Methods: Cross-sectional analysis including 233 adults with T1D using CGM. We assessed CGM metrics by gender, age group (18 to <30 years vs. ≥30 years), insulin delivery method (multiple daily injections vs. continuous subcutaneous insulin infusion [CSII]) and sensor type (iscCGM vs. rtCGM), working days versus weekends, and daytime versus night-time using multivariable linear regression models (adjusted for demographic variables) or Wilcoxon signed-rank test. Results: Overall, 79/21% of T1D patients used iscCGM/rtCGM. Those aged ≥30 years spent more time in range (TIR [70-180 mg/dL] 54% vs. 49%) and hypoglycemic range <70 mg/dL (7% vs. 5%), less time in hyperglycemic range >180 mg/dL (38% vs. 46%) and had a lower glucose variability (coefficient of variation [CV] 36% vs. 37%) compared with adults aged <30 years. We found no significant differences between genders. Multivariable regression models revealed the highest Time In Range (TIR) and lowest time with sensor glucose >250 mg/dL, CV and daytime-night-time differences in those treated with CSII and rtCGM. Glucose profiles were slightly more favorable on working days. Conclusions: In our real-world data, rtCGM versus iscCGM was associated with a higher percentage of TIR and improved metabolic stability. Differences in ambulatory glucose profiles on working and weekend days may indicate lifestyle habits affecting glycemic stability. Real-life CGM results should be included in benchmarking reports in addition to hemoglobin A1c (HbA1c) and history of hypoglycemia.
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Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1 , Insulina/administración & dosificación , Adolescente , Adulto , Austria , Glucemia , Estudios Transversales , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Alemania , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Estudios Prospectivos , Sistema de Registros , Suiza , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Antiviral therapy can stop progression of liver fibrosis and partially reverse it. Non-invasive methods have shown good diagnostic accuracies for the assessment of liver fibrosis. First studies have shown that transient elastography (TE) can be used to monitor fibrosis after antiviral therapy. Acoustic-Radiation-Force-Impulse (ARFI)-Imaging is an elastography method integrated in a conventional ultrasound machine. The aim of the present study was to demonstrate a significant difference of ARFI-values in patients with sustained-virological-response (SVR) as compared to patients without. METHOD: Ninety-eight patients infected with chronic hepatitis C virus (HCV) who had completed antiviral treatment were prospectively included in the study and received ARFI-imaging, TE and laboratory evaluation. RESULTS: Significantly lower ARFI and TE values were observed for 47 patients with SVR as compared to 51 patients without SVR (1.37 m/s vs. 2.00,p=0.0021; 4.9 kPa vs. 11.1 kPa,p<0.001), respectively. CONCLUSIONS: Liver stiffness values and shear wave velocity using ultrasound-based elastography methods are different in patients with SVR as compared to patients without SVR after antiviral therapy for chronic hepatitis C. However, the causes of this difference (fibrosis regression, cytolysis, baseline fibrosis) remain unclear and require further evaluation in future studies.
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Antivirales/uso terapéutico , Diagnóstico por Imagen de Elasticidad/métodos , Hepatitis C Crónica/diagnóstico por imagen , Hepatitis C Crónica/tratamiento farmacológico , Adulto , Anciano , Estudios Transversales , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/complicaciones , Humanos , Interferón-alfa/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ribavirina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]). METHODS: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion. RESULTS: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20). CONCLUSIONS: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations.
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Diagnóstico por Imagen de Elasticidad , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Cirrosis Hepática/sangre , Cirrosis Hepática/patología , Adulto , Alanina Transaminasa/sangre , Antirretrovirales/efectos adversos , Apolipoproteína A-I/sangre , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Biomarcadores/sangre , Coinfección/complicaciones , Intervalos de Confianza , Femenino , Haptoglobinas/metabolismo , Humanos , Cirrosis Hepática/etiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , alfa-Macroglobulinas/metabolismo , gamma-Glutamiltransferasa/sangreRESUMEN
INTRODUCTION: More than 180 million people worldwide are infected with the chronic hepatitis C virus (HCV), a major cause of liver cirrhosis, and its life-threatening complications including liver failure, portal hypertension and hepatocellular carcinoma. For patients infected with HCV genotype 1, the chances of a sustained virologic response (SVR) with the previous standard of care treatment (Peg-IFN-α + ribavirin) are only 40 - 50%. Neither drug targets a specific HCV protein, and treatment is not only compromised by insufficient SVR rates but also associated with several side effects. With a better understanding of the HCV life-cycle, and of the structural features of HCV proteins, several promising direct antiviral drugs (DAAs) have entered clinical development. AREAS COVERED: This review summarizes the clinical development of telaprevir and discusses the possible role of telaprevir in combination with Peg-IFN-α and ribavirin as a new standard treatment against HCV infection, as well as any possible challenges in the future. EXPERT OPINION: Triple therapy, with telaprevir in combination with Peg-IFN-α + ribavirin, is the new standard for chronic hepatitis C treatment in genotype 1-infected patients. At present, there are several next-generation DAAs in clinical development in combination with Peg-IFN-α. The future, however, may also include new treatment strategies, such as oral DAA combinations.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Interferón-alfa/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ribavirina/uso terapéuticoRESUMEN
BACKGROUND: MicroRNA-122 is a liver specific microRNA and is elevated in the sera of patients with chronic hepatitis C virus infection. Hepatic microRNA-122 levels have been described to be reduced in patients with non-response to antiviral treatment with pegylated interferon-α and ribavirin. AIM: Assessment of differences in serum microRNA-122 levels in patients with sustained virological response and non-response. METHODS: RNA was extracted from pretreatment serum samples and microRNA-122 and microRNA-16 levels were measured by quantitative PCR and compared in patients with sustained virological response and non-response. RESULTS: The levels of microRNA-122 and microRNA-16 in the sera did not differ between patients with sustained virological response and non-response. CONCLUSION: Serum microRNA-122 is not a suitable marker for treatment response prediction to combination therapy with pegylated interferon-α and ribavirin in patients with chronic hepatitis C virus infection.
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Antivirales/uso terapéutico , Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , MicroARNs/sangre , Adulto , Anciano , Alanina Transaminasa/sangre , Biomarcadores/sangre , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/virología , Humanos , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Recombinantes/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribavirina/uso terapéuticoRESUMEN
Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last few years. Combination therapy with pegylated interferon (PEG-IFN)-α plus ribavirin (RBV) has been the standard of care (SoC) treatment in the past few years. Several viral and host factors have been associated with treatment failure, including age, male gender, ethnicity, genotype, IL28B genotype, steatosis, obesity and insulin resistance. Several studies have also shown that in patients who fail treatment, several interferon-stimulated genes are upregulated before treatment. Recently, the NS3/4A protease inhibitors telaprevir and boceprevir have been approved and are considered the new SoC therapy in combination with PEG-IFN-α/RBV in HCV genotype 1 treatment-naïve patients, as well as in previously treated patients, with significant improvements in SVR rates. The REALIZE phase III trial with telaprevir in previously treated patients showed SVR rates of 83-88% in prior relapsers, 54-58% in prior partial responders and, 29-33% in prior non-responders.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Prolina/análogos & derivados , Ribavirina/uso terapéutico , Inhibidores de Serina Proteinasa/uso terapéutico , Adulto , Anciano , Anemia/inducido químicamente , Anemia/terapia , Ensayos Clínicos Fase III como Asunto , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Prolina/efectos adversos , Prolina/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Recurrencia , Enfermedades de la Piel/inducido químicamente , Insuficiencia del Tratamiento , Resultado del Tratamiento , Replicación Viral/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC. METHODOLOGY/PRINCIPAL FINDINGS: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (râ=â-0.494, Pâ=â0.00002), alanine aminotransferase (ALT) (râ=â-0.309, Pâ=â0.007), aspartate aminotransferase (râ=â-0.495, Pâ=â0.000007), bilirubin (râ=â-0.362, Pâ=â0.002), international normalized ratio (râ=â-0.338, Pâ=â0.034) and γ-glutamyltransferase (râ=â-0.244, Pâ=â0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dC(T) of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUCâ=â0.758) with a sensitivity of 53.3% and a specificity of 95.2%. CONCLUSIONS/SIGNIFICANCE: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.
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Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/complicaciones , Hepatitis C Crónica/sangre , Hepatitis C Crónica/complicaciones , Inflamación/sangre , Neoplasias Hepáticas/sangre , MicroARNs/sangre , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Biomarcadores/sangre , Carcinoma Hepatocelular/patología , Estudios de Cohortes , Femenino , Hepatitis C Crónica/enzimología , Hepatitis C Crónica/patología , Humanos , Inflamación/complicaciones , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Necrosis , Reproducibilidad de los Resultados , Albúmina Sérica/metabolismo , gamma-Glutamiltransferasa/sangreRESUMEN
BACKGROUND: Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance. OBJECTIVES: Potential persistence of resistance mutations during long-term follow-up should be analyzed. STUDY DESIGN: Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment. RESULTS: After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S+R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up. CONCLUSIONS: In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.
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Farmacorresistencia Viral , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Mutación Missense , Oligopéptidos/administración & dosificación , Prolina/análogos & derivados , Proteínas no Estructurales Virales/genética , Antivirales/administración & dosificación , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C/virología , Humanos , Estudios Longitudinales , Prolina/administración & dosificación , ARN Viral/genética , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Current therapy options for patients with chronic hepatitis C virus (HCV) infection genotype 1 are effective in <50%. Danoprevir (ITMN-191/RG7227) is a potent, selective, and orally active inhibitor of the HCV NS3/4A serine protease. METHODS: The safety and antiviral efficacy of danoprevir was examined over 14 days in combination with pegylated interferon α-2a (180 µg once weekly) and ribavirin (1000-1200 mg/day) in a double-blind, placebo-controlled, phase 1b, multiple ascending dose study consisting of 6 dose cohorts (400 mg, 600 mg, and 900 mg twice daily and 100 mg, 200 mg, and 300 mg 3 times daily). RESULTS: Danoprevir in combination with pegylated interferon α-2a and ribavirin was safe and generally well tolerated. The median change in HCV RNA level from baseline to the end of treatment with danoprevir at 400 mg, 600 mg, and 900 mg twice daily was -4.7 log(10) IU/mL, -5.4 log(10) IU/mL, and -5.3 log(10) IU/mL, respectively, and at 100 mg, 200 mg, and 300 mg 3 times daily was -5.5 log(10) IU/mL, -5.7 log(10) IU/mL, and -5.6 log(10) IU/mL, respectively. Placebo administered in combination with standard of care resulted in median decrease in HCV RNA level of -2.6 log(10) IU/mL (with twice daily regimen) and -2.0 log(10) IU/mL (with 3 times daily regimen). CONCLUSIONS: Our study showed substantial antiviral efficacy of danoprevir in combination with pegylated interferon α-2a and ribavirin. Exploration of the safety and antiviral efficacy of danoprevir in longer clinical studies is warranted.
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Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Lactamas/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Sulfonamidas/uso terapéutico , Antivirales/administración & dosificación , Ciclopropanos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Isoindoles , Lactamas/administración & dosificación , Lactamas/efectos adversos , Lactamas Macrocíclicas , Polietilenglicoles/administración & dosificación , Prolina/análogos & derivados , Proteínas Recombinantes , Ribavirina/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Proteínas no Estructurales ViralesRESUMEN
OBJECTIVES: The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection. METHODS: RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis. RESULTS: Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA. CONCLUSIONS: The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver.
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Hepatitis C Crónica/sangre , Hepatitis C Crónica/patología , Hígado/patología , MicroARNs/sangre , Adulto , Anciano , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Biomarcadores/sangre , Femenino , Hepatitis C Crónica/complicaciones , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Necrosis/sangre , Albúmina Sérica/metabolismoRESUMEN
BACKGROUND & AIMS: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. METHODS: Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype. CONCLUSIONS: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
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Antivirales/administración & dosificación , Proteínas Portadoras/antagonistas & inhibidores , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Lactamas/administración & dosificación , Inhibidores de Serina Proteinasa/administración & dosificación , Sulfonamidas/administración & dosificación , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto , Anciano , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Antivirales/sangre , Ciclopropanos , Método Doble Ciego , Farmacorresistencia Viral/genética , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Hepacivirus/genética , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular , Isoindoles , Lactamas/efectos adversos , Lactamas/sangre , Lactamas Macrocíclicas , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Prolina/análogos & derivados , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/administración & dosificación , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/sangre , Sulfonamidas/efectos adversos , Sulfonamidas/sangre , Carga Viral/efectos de los fármacos , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND/AIM: Insulin resistance (IR) is a major predictor of treatment failure in patients with hepatitis C virus (HCV) infection treated with peginterferon/ribavirin. The aim of this study was to evaluate the short-term effect of an HCV protease inhibitor monotherapy on IR in parallel with an antiviral effect. PATIENTS/METHODS: In a phase 1b placebo-controlled study, four cohorts of treatment-naïve patients with genotype 1 HCV received danoprevir (ITMN-191/RG7227), a protease inhibitor, or placebo (8/2 patients in each cohort respectively) in a gelatin capsule every 12 h (100, 200 mg) or 8 h (100, 200 mg) for 14 days. A fifth cohort including prior non-responders to peginterferon/ribavirin was similarly randomised to receive placebo or 300 mg danoprevir every 12 h. IR was assessed with the homeostasis model (HOMA-IR) at baseline and days 7, 14 and 15. RESULTS: Serum HCV-RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p<0.0001). At baseline, mean±SD serum HCV-RNA level and mean±SD HOMA-IR score were 6.2±0.5 log(10) IU/ml and 3.8±1.9, respectively. At the end of 14 days of monotherapy the mean±SD decrease in viral load was 2.2±1.3 log(10) IU/ml (p<0.0001) in patients who received the active drug (n=40). In parallel, the mean±SD HOMA-IR score also decreased in these patients by 1.6±1.1 (p<0.0001), with a close correlation between the extent of HOMA-IR improvement and the decrease in viral load. By contrast, serum HCV-RNA and HOMA-IR remained unchanged in patients who received placebo (n=10; 6.3±0.5 log(10) IU/ml and 3.8±2.5, respectively). CONCLUSION: HCV protease inhibitor may restore insulin sensitivity in patients with genotype 1 HCV. The place of insulin sensitisers remains to be determined in the era of triple therapy.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Lactamas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Ciclopropanos , Femenino , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/fisiopatología , Hepatitis C Crónica/virología , Humanos , Isoindoles , Lactamas Macrocíclicas , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , ARN Viral/sangre , Carga Viral/fisiología , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
The hepatitis C virus (HCV) nonstructural (NS) protein 4B is known for protein-protein interactions with virus and host cell factors. Only little is known about the corresponding protein binding sites and underlying molecular mechanisms. Recently, we have predicted a putative basic leucine zipper (bZIP) motif within the aminoterminal part of NS4B. The aim of this study was to investigate the importance of this NS4B bZIP motif for specific protein-protein interactions. We applied in silico approaches for 3D-structure modeling of NS4B-homodimerization via the bZIP motif and identified crucial amino acid positions by multiple sequence analysis. The selected sites were used for site-directed mutagenesis within the NS4B bZIP motif and subsequent co-immunoprecipitation of wild-type and mutant NS4B molecules. Respective interaction energies were calculated for wild-type and mutant structural models. NS4B-homodimerization with a gradual alleviation of dimer interaction from wild-type towards the mutant-dimers was observed. The putative bZIP motif was confirmed by a co-immunoprecipitation assay and western blot analysis. NS4B-NS4B interaction depends on the integrity of the bZIP hydrophobic core and can be abolished due to changes of crucial residues within NS4B. In conclusion, our data indicate NS4B-homodimerization and that this interaction is facilitated by the aminoterminal part containing a bZIP motif.
Asunto(s)
Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Secuencia de Aminoácidos , Inmunoprecipitación , Leucina Zippers/fisiología , Datos de Secuencia Molecular , Unión Proteica , Multimerización de Proteína/genética , Multimerización de Proteína/fisiologíaRESUMEN
BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Anciano , Antivirales/efectos adversos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Polietilenglicoles/efectos adversos , ARN Viral/sangre , Proteínas Recombinantes , Recurrencia , Ribavirina/efectos adversos , Carga Viral , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Left ventricular diastolic dysfunction has been reported in patients with liver cirrhosis. Although conventional Doppler echocardiography has been used to assess diastolic filling dynamics, this technique is limited in diagnosing left ventricular diastolic dysfunction. The aim of the study was to validate the N-terminal propeptide of the brain natriuretic peptide (NT-proBNP) in predicting left ventricular diastolic dysfunction diagnosed by tissue Doppler imaging in patients with chronic liver disease. METHODS: In 64 patients, left ventricular diastolic dysfunction was classified using tissue Doppler imaging and serum levels of NT-proBNP were measured. RESULTS: Left ventricular diastolic dysfunction was found in 25 of 31 (80.6%) patients with severe liver fibrosis/cirrhosis versus 2 of 8 (25.0%) patients with moderate and 6 of 25 (24.0%) patients with mild liver fibrosis (P<0.001). Mean NT-proBNP levels were 407.1+/-553.4 pg/ml in patients with severe fibrosis/cirrhosis as compared with 60.8+/-54.9 pg/ml and 55.4+/-41.4 pg/ml in patients with mild and moderate fibrosis (P=0.001). NT-proBNP was most accurate in predicting advanced left ventricular diastolic dysfunction with an area under the receiver-operating characteristic curve of 0.90 (95% confidence interval, 0.77-1.0; P<0.001). A cutoff value of greater than 290 pg/ml was highly predictive of advanced left ventricular diastolic dysfunction. CONCLUSION: NT-proBNP is a useful marker in detecting advanced left ventricular diastolic dysfunction in patients with chronic liver disease. Patients with severe liver fibrosis/cirrhosis and NT-proBNP levels exceeding 290 pg/ml should undergo further cardiac evaluation.
Asunto(s)
Cirrosis Hepática/complicaciones , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Disfunción Ventricular Izquierda/etiología , Adulto , Anciano , Biomarcadores/sangre , Enfermedad Crónica , Ecocardiografía Doppler de Pulso/métodos , Electrocardiografía , Femenino , Humanos , Cirrosis Hepática/sangre , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
OBJECTIVE: Neopterin is a marker of monocyte/macrophage activity. Alanine aminotransferase (ALAT) is a marker of hepatocyte injury. The aim of this study was to determine changes in neopterin and ALAT levels, as markers of inflammation, in two ancillary studies during two-phase 1b trials of hepatitis C virus (HCV) NS3.4A protease inhibitor telaprevir (VX-950), with or without peginterferon alfa-2a (Peg-IFN). MATERIAL AND METHODS: Fifty-four chronic hepatitis C patients (genotype 1) received placebo or telaprevir, with or without Peg-IFN, for 14 days in two multiple-dose studies. RESULTS: During administration of telaprevir, every patient demonstrated a >2-log decrease in HCV RNA. Mean neopterin and ALAT levels decreased in all four groups receiving telaprevir alone. In contrast, mean neopterin levels increased and ALAT levels decreased in the Peg-IFN plus telaprevir and Peg-IFN plus placebo groups. CONCLUSIONS: These data suggest that treatment of chronic hepatitis C patients with an HCV NS3.4A protease inhibitor ameliorates inflammation. The increase in neopterin levels and the decrease in ALAT levels during administration of Peg-IFN with or without telaprevir are in accordance with earlier observations showing that IFN reduces hepatocyte injury but increases monocyte/macrophage activity. The IFN-mediated immunomodulatory effects appear to remain intact when IFN is combined with telaprevir.
Asunto(s)
Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Mediadores de Inflamación/sangre , Interferón-alfa/administración & dosificación , Oligopéptidos/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Alanina Transaminasa/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hepacivirus/efectos de los fármacos , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/diagnóstico , Humanos , Interferón alfa-2 , Pruebas de Función Hepática , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neopterin/sangre , Proteínas Recombinantes , Valores de Referencia , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Proteínas no Estructurales ViralesRESUMEN
Almost half of the patients who have chronic hepatitis C cannot be cured with the current standard treatment. Recent progress in structure determination of HCV proteins and development of a subgenomic replicon system and a cell culture infectious HCV clone enabled the development of a specifically targeted antiviral therapy for hepatitis C (STAT-C). Many HCV-specific compounds are under investigation in preclinical and clinical trials. The development of agents in different classes may allow construction of antiviral combinations that enhance the effectiveness of antiviral treatment, reduce the duration of treatment, and, eventually, may even avoid the use of interferon-alfa.
Asunto(s)
Antivirales/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Evaluación de Medicamentos , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hepacivirus/genética , Hepatitis C/virología , Humanos , ARN Viral/efectos de los fármacos , ARN Viral/genéticaRESUMEN
BACKGROUND/AIMS: The efficacy of pegylated interferon alpha and ribavirin in HBV/HCV co-infected patients is unknown. METHODS: Nineteen patients with chronic HBV/HCV co-infection (HBsAg and HCV-RNA positive; 10 HCV-genotype 1; 9 HCV-genotype 2 or 3) were included in this prospective multicenter pilot study. Baseline HBV-DNA was negative in 13 individuals. All patients received weight-adjusted PEG-IFN-alpha2b and ribavirin for 48 weeks. RESULTS: In the intent-to-treat analysis, a biochemical and an HCV-RNA response were observed in 12 and 14 patients, respectively (63% and 74%). At the end of the treatment as well as at the end of the follow-up the HCV-RNA response was 93% (14/15) in patients adherent to therapy (86% in genotype 1 and 100% in genotypes 2 and 3 infection). Two of the five initially HBV-DNA positive patients with follow-up available were HBV-DNA negative at follow-up week 24. In contrast, HBV-DNA became detectable after the clearance of HCV in four initially HBV-DNA negative patients. CONCLUSIONS: Combination therapy with PEG-IFN-a2b and ribavirin is highly effective in inducing a virological response concerning HCV in patients with HBV/HCV co-infection. However, HBV replication may increase after the clearance of HCV and thus close monitoring for both the viruses is recommended even in patients with initially undetectable HBV-DNA.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Ribavirina/administración & dosificación , Adulto , Anciano , Antivirales/efectos adversos , ADN Viral/sangre , Femenino , Hepatitis B Crónica/virología , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles , Estudios Prospectivos , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/efectos adversosRESUMEN
UNLABELLED: Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa-2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa-2a (n = 8). Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa-2a was given as weekly 180 mug subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log(10) (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log(10) (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log(10) (range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a. The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off-study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa-2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa-2a group. CONCLUSION: This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa-2a.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Adolescente , Adulto , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Antivirales/farmacocinética , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Interferón-alfa/farmacocinética , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Oligopéptidos/farmacocinética , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacocinética , ARN Viral/sangre , Proteínas Recombinantes , Transaminasas/sangreRESUMEN
UNLABELLED: Telaprevir (VX-950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (>or=5%), mutations were identified that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon-alpha-2a (PEG-IFN-alpha-2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG-IFN-alpha-2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. CONCLUSION: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild-type virus, which uncovers pre-existing telaprevir-resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG-IFN-alpha-2a inhibited both wild-type and resistant variants. In the present study, every patient who began PEG-IFN-alpha-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive to PEG-IFN-alpha-2a and ribavirin.