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The impact of direct-acting antiviral (DAA) therapies on fibrosis regression remains uncertain. In the current study, we prospectively evaluated dynamics of liver stiffness by transient elastography (TE) in patients with chronic HCV infection receiving DAA-based treatment. Patients (260) were enrolled in the German Hepatitis C-Registry (DHC-R), a national multicentre real-world cohort. Liver stiffness (LS) was assessed at baseline, end of treatment (EOT) and 24 weeks after EOT (FU24) by TE. Biochemical, virological and clinical data were obtained in parallel. In patients with SVR, there was a significant improvement of LS between baseline (median [range], 8.6 [1.7-73.5] kPa) and FU24 (7.9 [1.7-75 kPa]; P < .0001) as well as between EOT (8.4 [1.7-73.5 kPa]) and FU24 [P < .0001]. Stratified by fibrosis stage, patients classified into F4 had higher magnitude of LS reduction between BL (median [range], 25.1 [13.5-73.5] kPa) and FU24 (21.5 [3.1-75] kPa; P = .002) compared to those with F2-F3 (8.9 [7.1-12.4] kPa and 8.8 [4.2-29.1]; P = .060) or F0-F1 (5.3 [1.7-7] kPa and 5.2 [1.7-7.7]; P = .064). In cirrhotic patients, low platelets were significantly associated with lack of liver stiffness improvement, both at EOT (P = .018) and at FU24 (P = .012). LS significantly correlated with ALT (r = .371), AST (r = .552), platelets (r = -.499), GGT (r = .250), bilirubin (r = .230), APRI score (r = .512), FIB-4 score (r = .517) and FORNS index (r = .562); P < .0001. Liver elastography improved significantly in our real-world cohort after DAA-based therapy. As LS correlates similarly with transaminase levels and serum fibrosis markers, it might reflect both reduction of necroinflammation and fibrosis regression.
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Diagnóstico por Imagen de Elasticidad , Hepatitis C Crónica , Hígado , Antivirales/uso terapéutico , Alemania , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Hígado/patología , Cirrosis Hepática/patología , Sistema de Registros , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
OBJECTIVE: Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. DESIGN: In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. RESULTS: Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11-32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). CONCLUSION: VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.
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Antivirales/uso terapéutico , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Replicación Viral/efectos de los fármacos , Adulto , Anciano , Algoritmos , Carcinoma Hepatocelular/prevención & control , Estudios de Cohortes , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Guanina/uso terapéutico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/mortalidad , Hepatitis B Crónica/virología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Cirrosis Hepática/virología , Neoplasias Hepáticas/prevención & control , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Endoscopic treatment for stenosis of an anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but the long-term outcomes and the risk factors for recurrence are unknown. All 374 patients who underwent OLT at Frankfurt University Hospital were screened for the occurrence of ABSs. ABSs were treated via the endoscopic insertion of a plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of the two (57.4%). The mean follow-up time was 151 weeks, and the mean survival time was 3.4 years. ABSs were observed in 47 patients (12.6%). The mean time from OLT to an ABS was 16.25 months (median = 3.25 months). The cumulative incidence rates for ABSs were 0.09 after 12 months, 0.10/24 m. and 0.11/36 m. In 12 cases (25.5%), ABSs were observed more than 12 months after OLT. ABSs recurred in 16 of the 47 patients (34%). The occurrence of an ABS 6 weeks or more after OLT was a significant predictor of ABS recurrence [P = 0.04, hazard ratio (HR) = 0.235]. There was a trend of hepatitis C virus (HCV) infections being predominant in patients experiencing ABS recurrence (30% for HCV etiology versus 4% for non-HCV etiology) in comparison with patients not experiencing recurrence (36% for HCV etiology versus 30% for non-HCV etiology, P > 0.05). The severity of the initial stricture predicted ABS recurrence (P = 0.046, HR = 2.78), but it did not influence overall survival. The long-term resolution of ABSs was observed in 45 of the 47 patients (95.7%), and ABS recurrence was treated with another attempt (n = 16 or 34%) or 2 more attempts (n = 1) at endoscopic treatment. In conclusion, the long-term success of the endoscopic treatment of ABSs is highly probable if recurrent strictures are again treated endoscopically. ABSs might occur late (>36 months) after OLT, and lifelong follow-up is essential for identifying OLT patients with ABSs.
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Anastomosis Quirúrgica/efectos adversos , Constricción Patológica/patología , Constricción Patológica/terapia , Endoscopía/métodos , Fallo Hepático/complicaciones , Trasplante de Hígado/efectos adversos , Enfermedades de las Vías Biliares/terapia , Femenino , Estudios de Seguimiento , Humanos , Fallo Hepático/terapia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Endoscopic treatment of stenosis of the anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but long term outcome and risk factors for recurrence are unknown. METHODS: All 374 patients who underwent OLT at Frankfurt University hospital were screened for occurrence of ABS. ABS was treated by endoscopic insertion of plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of both (57.4%). Long-term outcome and risk factors for occurrence and recurrence of ABS was determined through competing risk analysis. Mean follow-up time was 151 weeks and mean survival was 3.4 years. RESULTS: ABS was observed in 47 patients (12.6%). Mean (median) time from OLT to ABS was 16.3 months (3.3 months). Cumulative incidence rates of ABS were 0.09 after 12 months, 0.10 after 24 months and 0.11 after 36 months. In 12 cases (25.5%), ABS was observed later than 12 months after OLT. ABS recurred in 14 of 47 (29%). Ocurrence of ABS more than six weeks after OLT was a significant predictor of ABS recurrence (p=0.04, H.R. 0.235). There was a trend of HCV infection to be predominant in patients with recurrence of ABS (30% HCV vs. 4% non-HCV) in comparison to patients with non-recurrence (HCV 36%, non-HCV 30%); p > 0.05. Severity of initial stricture predicted recurrence of ABS (p = 0.046, HR=2.78), but did not influence overall survival. Long-term resolution of ABS was observed in 45 of 47 patients (95.7%), recurrence of ABS was treated with a second (n= 16, 34%), or a third endoscopic treatment attempt (1). CONCLUSION: Long-term success of endoscopic treatment of ABS is highly probable if recurrent strictures are again treated endoscopically. ABS might occur late (>36 months) after OLT and life-long follow-up is essential in OLT patients to identify patients with ABS. © 2013 American Association for the Study of Liver Diseases.
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Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.
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UNLABELLED: Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA-naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA-naïve population consisted of 243 patients, whereas 90 were NA-experienced. Virological response (VR) (HBV DNA<80 IU/mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)-positive and in 89%, 98%, and 99% of HBeAg-negative NA-naïve patients at weeks 48, 96, and 144, respectively. Thirty-six of 175 (21%) NA-naïve patients with at least 48 weeks of follow-up had a detectable load at week 48 (partial virological response [PVR]). Twenty-nine (81%) patients with PVR reached VR during prolonged ETV monotherapy, and none of them developed ETV-resistance. Among 22 patients with HBV DNA<1,000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared with eight of 14 (57%) patients with HBV DNA≥1,000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow-up, and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis. CONCLUSION: ETV monotherapy can be continued in NA-naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long-term ETV leads to a virological response in the vast majority of patients.
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Antivirales/uso terapéutico , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Adulto , Estudios de Cohortes , Femenino , Guanina/uso terapéutico , Hepatitis B Crónica/virología , Humanos , Masculino , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Acoustic radiation force impulse (ARFI) imaging is a new non-invasive, ultrasound-based method for the evaluation of liver fibrosis and cirrhosis. AIM: To determine the diagnostic accuracy of ARFI imaging, transient elastography (TE) and Fibrotest for the evaluation of complications in patients with cirrhosis. METHODS: A total of 166 patients (109 male, mean age: 54 ± 11 years) with chronic liver disease and established cirrhosis were included in this study. ARFI-imaging of the liver and spleen, TE and Fibrotest were performed in all patients. In addition, clinical, laboratory and morphological parameters, including MELD/Child-Pugh scores, presence of oesophageal varices and hepatocellular carcinoma, history of variceal bleeding and history of hepatic encephalopathy were recorded. RESULTS: Acoustic radiation force impulse liver was significantly correlated with ARFI spleen (r = 0.48, P < 0.001), TE (r = 0.75, P < 0.001) and Fibrotest (r = 0.21, P = 0.006). The diagnostic accuracy (AUROC) for the diagnosis of large oesophageal varices was 0.58 (95% CI: 0.48-0.67), 0.58 (0.49-0.67), 0.53 (0.44-0.63) and 0.50 (0.41-0.59) for ARFI liver, spleen, TE and Fibrotest respectively (P > 0.20). The AUROC for the detection of hepatocellular carcinoma (HCC) was 0.54 (0.39-0.70), 0.58 (0.44-0.73), 0.56 (0.40-0.73) and 0.72 (0.60-0.84) respectively (P > 0.20). Multiple logistic regression analysis showed that ARFI spleen better predicted the presence of large oesophageal varices and HCC compared with ARFI liver. CONCLUSIONS: The diagnostic accuracy of ARFI liver and spleen was comparable to TE and Fibrotest for the detection of complications in patients with cirrhosis.
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Carcinoma Hepatocelular/diagnóstico , Diagnóstico por Imagen de Elasticidad/métodos , Enfermedad Hepática en Estado Terminal/diagnóstico , Várices Esofágicas y Gástricas/diagnóstico , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Adulto , Anciano , Biomarcadores/metabolismo , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/metabolismo , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/metabolismo , Femenino , Fibrosis/complicaciones , Fibrosis/diagnóstico , Fibrosis/metabolismo , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Juego de Reactivos para DiagnósticoRESUMEN
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
BACKGROUND AND AIM: The standard of hepatitis C antiviral therapy combines pegylated interferon-α with ribavirin. This polar guanosine analog improves the sustained virological response (SVR) rates, but may induce hemolytic anemia. As its pharmacokinetics depend on facilitated transmembrane transport, we assessed whether variants in genes that code for concentrative (concentrative nucleoside transporters 2 and 3 coded by SLC28A2 and SLC28A3, respectively) and equilibrative nucleoside transporters (equilibrative nucleoside transporters 1 and 2 coded by SLC29A1 and SLC29A2, respectively) are associated with the therapy response and side effects. METHODS: Patients (n=169) chronically infected with the hepatitis C virus genotype 1, treated with standard doses of pegylated interferon-α and weight-based doses of ribavirin for up to 48 weeks, were genotyped for 21 variants in nucleoside transporter genes SLC28A2, SLC28A3, SLC29A1, and SLC29A2, selected to include reported functional variants and to span the complete gene loci. The presence or absence of a SVR (n=169) and a relevant decrease (>3 g/dl, n=115) in blood hemoglobin were associated with the genotypes. RESULTS: The variant SLC28A3 haplotype rs10868138G/rs56350726T (allelic frequency 0.074) was associated with a lower incidence (35.5%) of relevant decreases (>3 g/dl) in blood hemoglobin than in noncarriers (64.3%; P=0.024, n=115). This protection against hemolytic anemia was not associated with decreased SVR rates (n=169). CONCLUSION: A genetic variant in SCL28A3 coding for the concentrative nucleoside transporter 3 protects patients with chronic hepatitis C against hemolytic anemia without affecting SVR in hepatitis C virus genotype 1.
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Anemia Hemolítica/inducido químicamente , Anemia Hemolítica/genética , Antivirales/efectos adversos , Tranportador Equilibrativo 1 de Nucleósido/genética , Transportador Equilibrativo 2 de Nucleósido/genética , Hepatitis C Crónica/tratamiento farmacológico , Proteínas de Transporte de Membrana/genética , Ribavirina/efectos adversos , Adulto , Anciano , Antivirales/uso terapéutico , Femenino , Estudios de Asociación Genética , Hemoglobinas/análisis , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Polimorfismo de Nucleótido Simple , Proteínas Recombinantes , Ribavirina/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. METHODS: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. RESULTS: During hospitalization, the platelet count was measured above 330,000/µl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. CONCLUSIONS: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.
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Hepatitis C Crónica/complicaciones , Cirrosis Hepática/complicaciones , Vena Porta , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Trombopoyetina/efectos adversos , Trombosis de la Vena/etiología , Angiografía de Substracción Digital , Femenino , Humanos , Persona de Mediana Edad , Receptores Fc , Receptores de Trombopoyetina/agonistas , Factores de Riesgo , Tomografía Computarizada por Rayos X , Trombosis de la Vena/diagnóstico por imagenRESUMEN
BACKGROUND & AIMS: Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. METHODS: Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. RESULTS: Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). CONCLUSIONS: We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.
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Hepatitis C Crónica/genética , Hepatitis C Crónica/cirugía , Interleucinas/genética , Trasplante de Hígado/efectos adversos , Adulto , Anciano , Alanina Transaminasa/sangre , Antivirales/administración & dosificación , Femenino , Genotipo , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/fisiopatología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferones , Cirrosis Hepática/etiología , Trasplante de Hígado/fisiología , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polimorfismo de Nucleótido Simple , ARN Viral/sangre , Proteínas Recombinantes/administración & dosificación , Recurrencia , Ribavirina/administración & dosificación , Donantes de Tejidos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: The hepatitis C virus (HCV) receptor CD81 is overexpressed on peripheral blood mononuclear cells (PBMC) in patients chronically infected with HCV compared with healthy controls, and expression declines during antiviral therapy. The aim of this study was to prospectively investigate CD81 expression on PBMC for early discrimination between sustained virologic response (SVR) and relapse (REL) to pegylated interferon alfa-2b and ribavirin treatment. METHODS: Sixty-one patients with chronic HCV infection (genotype, GT, 1 and low baseline viremia <600,000 IU/ml, n = 30; GT 2 or 3, n = 31) were investigated. CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was measured at baseline, therapy week (TW) 4 and 12 during antiviral therapy by fluorescence-activated cell sorting (FACS) analysis. RESULTS: Baseline levels of CD81 on CD4(+), CD8(+), and CD56(+) cells were similar between patients who achieved a SVR (n = 42) and those who relapsed (n = 19). On CD19(+) cells, baseline CD81 expression was higher in patients with SVR than in patients with virologic relapse (REL) (p < 0.006). A cutoff value of 720 relative fluorescence units (RFU) discriminated correctly between SVR and REL with a sensitivity and specificity of 73.7% and 66.7%, respectively. SVR patients showed a significant decline of CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells (p < 0.01 for all) while in REL patients a significant decline of CD81 expression was observed on CD8(+) and CD56(+) cells, only (p = 0.050 and p = 0.038, respectively). CONCLUSIONS: The current study confirms significant down-regulation of CD81 expression on different lymphocyte subpopulations during pegylated interferon alfa-based antiviral therapy in patients with chronic hepatitis C. Baseline CD81 expression on CD19(+) cells was found to discriminate between SVR and REL.
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Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Tetraspanina 28/metabolismo , Adulto , Biomarcadores/metabolismo , Regulación hacia Abajo , Femenino , Hepatitis C Crónica/metabolismo , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Sensibilidad y Especificidad , Carga ViralRESUMEN
BACKGROUND: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. OBJECTIVE: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. METHODS: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. RESULTS: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). CONCLUSION: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
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OBJECTIVES: The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation. PATIENTS AND METHODS: We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels. RESULTS: Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohn's disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged. CONCLUSIONS: Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Pirrolidinonas/uso terapéutico , Ritonavir/uso terapéutico , Tacrolimus/administración & dosificación , Adulto , Fármacos Anti-VIH/farmacocinética , Interacciones Farmacológicas , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Inmunosupresores/farmacocinética , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Pirrolidinonas/farmacocinética , Raltegravir Potásico , Estudios Retrospectivos , Ritonavir/farmacocinética , Suero/química , Tacrolimus/farmacocinéticaRESUMEN
Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral efficacy and a high genetic barrier to viral resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited. Here, we report on 16 patients with liver cirrhosis and chronic hepatitis B who were treated with entecavir. Five of these patients developed lactic acidosis during entecavir treatment. All patients who developed lactic acidosis had highly impaired liver function (Model for End-Stage Liver Disease [MELD] score >or= 20). Lactic acidosis (lactate 26-200 mg/dL, pH 7.02-7.40, base excess -5 mmol/L to -18 mmol/L) occurred between 4 and 240 days after treatment initiation with entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18. The MELD score correlated with the development of lactic acidosis (P < 0.005) as well as its single parameters bilirubin, international normalized ratio, and creatinine. In contrast, Child-Pugh Score did not correlate with the development of lactic acidosis. Our data indicate that entecavir should be applied cautiously in patients with impaired liver function.
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Acidosis Láctica/inducido químicamente , Antivirales/efectos adversos , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Fallo Hepático/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Guanina/efectos adversos , Hepatitis B Crónica/fisiopatología , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Chronic infection with the hepatitis C virus (HCV) represents one of the major causes for end-stage liver disease worldwide. Although liver transplantation offers an effective treatment, HCV reinfection of the transplanted graft is a critical and almost inevitable complication with major influence on graft- and patient survival. Pre-transplant antiviral therapy in advanced liver disease is limited by poor tolerance and only applicable to mildly decompensated patients but was able to show promising results in patients reaching negative viral load when undergoing transplantation. Prophylactic therapy with HCV antibodies during the anhepatic phase has not been shown to be effective in studies to date. Antiviral therapy after transplantation but before evidence of reinfection, so called pre-emptive treatment, is limited by frequent complications and a high rate of side effects. The mainstay of management represents directed antiviral therapy after evidence of recurrence of chronic Hepatitis C. With a combination therapy of pegylated interferon and ribavirin, sustained virologic response rates of 25-45% are achieved. However, tolerability is often poor, and the need of dose reduction is frequent. To date, there is no general consensus on modality, timing and dosing of antiviral treatment of HCV in patients with advanced liver disease and after liver transplantation. More randomised, controlled trials are needed. Moreover, upcoming new treatment approaches, e.g. specifically targeted antiviral therapy for hepatitis C (STAT-C) with HCV-specific polymerase and protease inhibitors, may represent a therapeutic alternative.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/patología , Trasplante de Hígado , Antivirales/efectos adversos , Quimioprevención/métodos , Quimioterapia Combinada , Humanos , Interferones/efectos adversos , Interferones/uso terapéutico , Ribavirina/efectos adversos , Ribavirina/uso terapéutico , Prevención Secundaria , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: NAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care. METHODS: The FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months. RESULTS: In this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%. CONCLUSIONS: This is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients. LAY SUMMARY: FLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease.
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UNLABELLED: The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1-infected patients (mean age, 46 +/- 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n = 352) or (B) placebo (n = 352), both in combination with 180 microg peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P = 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). CONCLUSION: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection.
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Amantadina/uso terapéutico , Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Amantadina/efectos adversos , Antivirales/efectos adversos , Aspartato Aminotransferasas/sangre , Quimioterapia Combinada , Femenino , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Selección de Paciente , Placebos , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
This chapter reviews the main chemotherapeutic strategies used against human infections caused by agents responsible for the most important chronic viral illnesses, namely hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). There is no doubt that most current knowledge about combination antiviral therapy has been developed in the battle against HIV. The availability of more than 20 antiretroviral drugs has permitted to explore their efficacy when given in combination, an opportunity that unfortunately has only been possible since recent years for chronic hepatitis C and still is in the early stages for chronic hepatitis B. However, new antiviral compounds targeting each of these viruses are developed rapidly and will provide further opportunities to explore the efficacy of combination antiviral therapy. While sufficient suppression of HIV RNA and HBV DNA can only be achieved by long-term administration of potent antiviral drugs, HCV RNA may be completely eradicated from the infected individual after a limited duration of treatment.