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BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune disease characterized by bile duct destruction that can progress to cirrhosis. A liver biopsy substudy was conducted in the PBC obeticholic acid (OCA) International Study of Efficacy (POISE) to determine the long-term effects of OCA on liver damage and fibrosis in patients with PBC. POISE is a phase 3, double-blind, placebo-controlled, randomized trial with a 5-year open-label extension that evaluated 5 to 10 mg OCA daily in patients who were intolerant or unresponsive to ursodeoxycholic acid. METHODS: Liver biopsy specimens were collected from 17 patients at time of enrollment in the double-blind phase and after 3 years of OCA treatment. Histologic evaluations were performed by 2 pathologists in a blinded, randomized fashion to determine the effects of OCA on fibrosis and other histologic parameters. Collagen morphometry assessments were performed by automated second harmonic generation and 2-photon excitation microscopy to observe quantitative measures of fibrosis. RESULTS: From the time of enrollment until 3 years of treatment, most patients had improvements or stabilization in fibrosis (71%), bile duct loss (76%), ductopenia (82%), ductular reaction (82%), interface hepatitis (100%), and lobular hepatitis (94%). Over the 3-year period, we found significant reductions in collagen area ratio (median, -2.1; first quartile, -4.6, third quartile, -0.3; P = .013), collagen fiber density (median, -0.8; first quartile, -2.5; third quartile, 0; P = .021), collagen reticulation index (median, -0.1; first quartile, -0.3; third quartile, 0; P = .008), and fibrosis composite score (median, -1.0; first quartile, -2.5; third quartile, -0.5; P = .002). CONCLUSIONS: A subanalysis of data from the POISE study showed that long-term OCA treatment in patients with PBC is associated with improvements or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry features (ClinicalTrials.gov no: NCT01473524 and EudraCT no: 2011-004728-36).
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Cirrose Hepática Biliar , Hepatopatias , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. METHODS: This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. RESULTS: At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. CONCLUSIONS: The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).
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Atorvastatina/administração & dosagem , Ácido Quenodesoxicólico/análogos & derivados , Lipoproteínas/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Idoso , Ácidos e Sais Biliares/metabolismo , Ácido Quenodesoxicólico/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Resultado do Tratamento , Estados UnidosRESUMO
Sustained virologic response (SVR) after direct-acting antiviral (DAA) therapy for chronic hepatitis C results in significant decreases in liver stiffness measured by transient elastography (TE). The aim of this study was to clarify if TE can guide post-SVR management in patients with advanced fibrosis or cirrhosis prior to treatment as current guidelines are unclear on the role of TE after SVR. In total, 84 patients with hepatitis C virus and advanced fibrosis or cirrhosis and from a single center underwent DAA treatment and achieved SVR. Overall, 62% had improved liver stiffness that was consistent with regression of at least one stage of fibrosis. In the cirrhosis group, 48% showed fibrosis regression by at least two stages by TE (<9.5 kPa). In the F3 fibrosis group, 39% regressed by at least two stages (<7 kPa). The median time from SVR to regression by TE was 1 year. Fifteen patients with liver biopsies prior to SVR underwent a biopsy after SVR; 13 of these patients had improved liver stiffness (to <9.5 kPa). The post-SVR liver biopsies of only 4 patients showed F1-F2 while 11 patients showed F3-F4; however, morphometry of the first 11 biopsied patients revealed that 10 patients had an average 46% decrease in collagen content. Conclusion: This is the first DAA study that also has paired liver biopsies showing fibrosis regression. After SVR is achieved, improvements in liver stiffness measured by TE are seen in a majority of patients with advanced fibrosis/cirrhosis within 2 years. TE improvements are overstated when compared to histologic staging but confirmed with morphometric analysis. It is unclear whether TE following SVR can reliably predict when patients no longer require advanced fibrosis/cirrhosis monitoring after SVR.
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Transarterial chemoembolization (TACE) is an effective palliative intervention that is widely accepted for the management of hepatocellular carcinoma (HCC). Post-TACE pulmonary complications resulting in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are rare events. Pulmonary complications after TACE are thought to be related to chemical injury subsequent to the migration of the infused ethiodized oil or chemotherapeutic agent to the lung vasculature, facilitated by arteriovenous (AV) shunts within the hyper-vascular HCC. We review herein the literature on pulmonary complications related to TACE for HCC. Post-TACE pulmonary complications have included pulmonary oil embolism, interstitial pneumonitis, chemical pneumonitis, ALI, ARDS, lipoid pneumonia, acute eosinophilic and neutrophilic pneumonia, bilious pleuritis, pulmonary abscess, pulmonary tumor embolism, and possibly pulmonary metastasis with HCC. The risk factors associated with post-TACE pulmonary complications identified in the literature include large hyper-vascular HCC with AV shunts, large-volume Lipiodol infusion, and embolization via the right inferior phrenic artery. However, the absence of known risk factors is not a guarantee against serious complications. An astute awareness of the potential post-TACE pulmonary complications should expedite appropriate therapeutic interventions and increase potential for early recovery.
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Lesão Pulmonar Aguda/etiologia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/efeitos adversos , Óleo Etiodado/efeitos adversos , Migração de Corpo Estranho/etiologia , Neoplasias Hepáticas/terapia , Embolia Pulmonar/etiologia , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/terapia , Carcinoma Hepatocelular/patologia , Óleo Etiodado/administração & dosagem , Migração de Corpo Estranho/diagnóstico , Migração de Corpo Estranho/terapia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/terapia , Fatores de Risco , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND & AIMS: Accumulating evidence indicates that microRNAs play a role in a number of disease processes including the pathogenesis of liver fibrosis in hepatitis C infection. Our goal is to add to the accruing information regarding microRNA deregulation in liver fibrosis to increase our understanding of the underlying mechanisms of pathology and progression. METHODS: We used next generation sequencing to profile all detectable microRNAs in liver tissue and serum from patients with hepatitis C, stages F1-F4 of fibrosis. RESULTS: We found altered expression of several microRNAs, in particular, miR-182, miR199a-5p, miR-200a-5p and miR-183 were found to be significantly upregulated in tissue from liver biopsies of hepatitis C patients with advanced fibrosis, stage F3 and F4, when compared with liver biopsies from patients with early fibrosis, stages F1 and F2. We also found miR-148-5p, miR-1260b, miR-122-3p and miR-378i among the microRNAs most significantly down-regulated from early to advanced fibrosis of the liver. We also sequenced the serum microRNAs; however, we were not able to detect significant changes in circulating microRNAs associated with fibrosis stage after adjusting for multiple tests. CONCLUSIONS: Adding measurements of tissue microRNAs acquired during routine biopsies will continue to increase our knowledge of underlying mechanisms of fibrosis. Our goal is that these data, in combination with studies from other researchers and future long-term studies, could be used to enhance the staging accuracy of liver biopsies and expand the surveillance of patients at increased risk for cancer and progression to advanced fibrosis.
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Hepatite C Crônica/genética , Cirrose Hepática/genética , Fígado/química , MicroRNAs/genética , Idoso , Biópsia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Marcadores Genéticos , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Fatores de Risco , Análise de Sequência de RNA , Fatores de TempoRESUMO
Chronic hepatitis C virus (HCV) infection afflicts a reported 170 million people worldwide and is often complicated by cirrhosis and hepatocellular carcinoma. Morbidity and mortality are decreased with the successful treatment of chronic HCV infection. Increased understanding of the HCV has allowed further development of new direct-acting antiviral (DAA) agents against the HCV and has also allowed the development of IFN-free oral treatment regimens. In late 2013 the first nucleotide polymerase inhibitor regimen with RBV alone for genotypes 2/3 and in combination with a 12-week regimen of PEG-IFN + RBV for genotypes 1, 4 was approved for use in the US. A number of promising new DAA regimens which are IFN-free are in phase 3 development and the first will likely be approved for use in the US in 2014. The currently approved regimens are discussed in detail and currently available data on future regimens are reviewed herein.
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Hepatite C Crônica/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Quimioterapia Combinada , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , HumanosRESUMO
Chronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (V(H)) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the V(H) genes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations.
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Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Hepatite C Crônica/imunologia , Tolerância Imunológica , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/patologia , Subpopulações de Linfócitos B/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulina M/sangue , Região Variável de Imunoglobulina/genética , Memória Imunológica , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND AIMS: Acute liver failure (ALF) is frequently complicated by cerebral oedema, systemic inflammation and multiorgan dysfunction. Vascular endothelial growth factor (VEGF) may stimulate liver regeneration but it can also be pro-inflammatory, activating endothelial cells and increasing permeability, actions mediated through Src kinase signalling. We therefore examined whether a Src inhibitor could have therapeutic potential in ALF. METHODS: Murine ALF was induced with azoxymethane. Liver pathology was graded by a blinded examiner and apoptosis quantified by immunohistochemistry. Cerebral VEGF expression was imaged using VEGF-green fluorescent protein transgenic mice. Circulating and macrophage-secreted VEGF levels were measured. Experimental animals received a Src inhibitor or vehicle controls. RESULTS: VEGF was undetectable in normal plasma but reached a mean of 835 pg/ml at grade III encephalopathy (P<0.001). Ammonia, lipopolysaccharide and interferon-gamma acted synergistically to enhance VEGF secretion by macrophages. Production of VEGF by cerebral cortical astrocytes increased with disease progression. Late treatment with inhibitors of Src or VEGF did not improve liver histology, encephalopathy or survival. However, early use of a Src kinase inhibitor significantly reduced hepatic injury, delayed encephalopathy and allowed 25% of mice to survive an otherwise lethal insult. CONCLUSION: Systemic and cerebral VEGF levels are significantly elevated during experimental ALF and may be exacerbated by hyperammonemia and macrophage activation. Early use of a Src inhibitor reduced hepatocellular injury and enabled survival, indicating such agents may have some promise in the treatment of ALF.
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Compostos de Anilina/farmacologia , Edema Encefálico/prevenção & controle , Encéfalo/efeitos dos fármacos , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Quinases da Família src/antagonistas & inibidores , Cloreto de Amônio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/enzimologia , Azoximetano , Encéfalo/enzimologia , Encéfalo/patologia , Edema Encefálico/induzido quimicamente , Edema Encefálico/enzimologia , Edema Encefálico/patologia , Células Cultivadas , Modelos Animais de Doenças , Fatores de Crescimento Endotelial/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Encefalopatia Hepática/enzimologia , Encefalopatia Hepática/prevenção & controle , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Interferon gama/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/enzimologia , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/enzimologia , Falência Hepática Aguda/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peptídeos Cíclicos/farmacologia , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Quinases da Família src/metabolismoRESUMO
Malignant and nonmalignant disorders may affect the liver, causing signs and symptoms ranging from mild increases of liver tests to fulminant hepatic failure. This article discusses the most common hematologic and oncologic disorders and their effect on the liver. The section on nonmalignant hematologic disorders includes the anemias, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation, malaria, Banti syndrome, the porphyrias, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. Malignant hematologic conditions include leukemias, lymphomas, and myeloproliferative disorders. Other conditions causing portal hypertension and hepatic metastases are also discussed. The most commonly encountered hepatic manifestations of hematologic and oncologic disorders are reviewed.
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Doenças Hematológicas/complicações , Neoplasias Hematológicas/patologia , Hepatopatias/complicações , Neoplasias Hepáticas/secundário , Doenças Hematológicas/fisiopatologia , Humanos , Hepatopatias/fisiopatologia , Neoplasias Hepáticas/fisiopatologiaRESUMO
UNLABELLED: Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of ≥1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels ≤3 × upper limit of the normal range; mean baseline activity and fibrosis scores were 1.8 and 1.7, respectively. Overall, 80% of patients received peginterferon alfa-2a monotherapy or peginterferon alfa-2a/ribavirin combination therapy. Mean treatment duration was 46 weeks. There was a positive correlation between the degree of virologic response and improvements in METAVIR activity and fibrosis, and an inverse correlation with worsening activity and fibrosis (all comparisons, P < 0.0001). Patients with SVR had the greatest histologic benefit. As a combined group, relapsers and patients with breakthrough had significantly greater benefits than nonresponders (activity, P = 0.0001; fibrosis, P = 0.003). Consistent with these results, a better histologic response was correlated with a shorter time to undetectable HCV RNA and a longer duration of viral suppression (all comparisons, P < 0.0001). CONCLUSION: In patients with chronic hepatitis C who were treated with interferon-based therapies, histologic benefits may be observed even in the absence of an SVR.
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Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Adulto , Feminino , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes , Resultado do TratamentoRESUMO
AIM: To investigate the utility of esophageal capsule endoscopy in the diagnosis and grading of esophageal varices. METHODS: Cirrhotic patients who were undergoing esophagogastroduodenoscopy (EGD) for variceal screening or surveillance underwent capsule endoscopy. Two separate blinded investigators read each capsule endoscopy for the following results: variceal grade, need for treatment with variceal banding or prophylaxis with beta-blocker therapy, degree of portal hypertensive gastropathy, and gastric varices. RESULTS: Fifty patients underwent both capsule and EGD. Forty-eight patients had both procedures on the same day, and 2 patients had capsule endoscopy within 72 h of EGD. The accuracy of capsule endoscopy to decide on the need for prophylaxis was 74%, with sensitivity of 63% and specificity of 82%. Inter-rater agreement was moderate (kappa = 0.56). Agreement between EGD and capsule endoscopy on grade of varices was 0.53 (moderate). Inter-rater reliability was good (kappa = 0.77). In diagnosis of portal hypertensive gastropathy, accuracy was 57%, with sensitivity of 96% and specificity of 17%. Two patients had gastric varices seen on EGD, one of which was seen on capsule endoscopy. There were no complications from capsule endoscopy. CONCLUSION: We conclude that capsule endoscopy has a limited role in deciding which patients would benefit from EGD with banding or beta-blocker therapy. More data is needed to assess accuracy for staging esophageal varices, PHG, and the detection of gastric varices.
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Endoscopia por Cápsula/métodos , Endoscopia do Sistema Digestório/métodos , Varizes Esofágicas e Gástricas/diagnóstico , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Varizes Esofágicas e Gástricas/prevenção & controle , Feminino , Humanos , Hipertensão Portal/diagnóstico , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Método Simples-CegoRESUMO
UNLABELLED: Fibrosis progression in chronic liver disease has usually been evaluated by liver biopsy using insensitive semiquantitative numerical scores. An alternative to this is to measure fibrous tissue quantitatively using morphometric image analysis. The aim of this study was to quantify fibrosis progression in a cohort of patients with treatment-refractory chronic hepatitis C enrolled in a placebo-controlled clinical trial of interferon gamma-1b (IFN-gamma 1b) for the treatment of advanced hepatic fibrosis. We used morphometry to quantify the amount of fibrous tissue in liver biopsies performed at baseline and after 48 weeks in 245 patients who had paired unfragmented, adequate-sized specimens and correlated the results with clinical and laboratory parameters. Eighty-seven patients were treated with placebo and 158 with IFN-gamma 1b. No effect of the drug on fibrosis was found in the trial, and so data from all 245 patients were combined for analysis. At baseline, 78% had cirrhosis; 22%, bridging fibrosis. The mean morphometrically determined collagen content increased by 58% between baseline and 48 weeks. There were statistically significant but weak correlations of fibrosis with platelet count, albumin, bilirubin, INR, and hyaluronic acid; however, changes in these did not correlate with or predict changes in fibrosis in the liver biopsy. CONCLUSION: In advanced chronic hepatitis C, fibrosis increases at a rapid pace that can only be detected by morphometry. This technique can be used in future therapeutic trials of agents to inhibit fibrosis progression.
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Hepatite C Crônica/patologia , Cirrose Hepática/patologia , Fígado/patologia , Biópsia , Hepatite C Crônica/complicações , Humanos , Processamento de Imagem Assistida por Computador , Cirrose Hepática/etiologia , Testes de Função HepáticaRESUMO
SciClone Pharmaceuticals and Verta are developing SCV-07, the lead in a series of immnunostimulants from Verta, for the potential treatment of tuberculosis and hepatitis C virus infection. Phase II clinical trials of the compound are ongoing.
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Adjuvantes Imunológicos/uso terapêutico , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Dipeptídeos/uso terapêutico , Tuberculose/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antivirais/administração & dosagem , Antivirais/farmacocinética , Ensaios Clínicos como Assunto , Dipeptídeos/administração & dosagem , Dipeptídeos/farmacocinética , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Hepatite C Crônica/tratamento farmacológico , Humanos , Injeções Intramusculares , Vírus Lassa/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Papillomaviridae/efeitos dos fármacos , Baço/citologia , Baço/efeitos dos fármacos , Timo/citologia , Timo/efeitos dos fármacosRESUMO
Anemia and decreased health-related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb < or = 12 g/dL) HCV-infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8-week double-blind phase (DBP), followed by an 8-week open-label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV-infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion, epoetin alfa provided clinically significant HRQL improvement in HCV-infected patients receiving IFN/RBV therapy.
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Anemia/tratamento farmacológico , Eritropoetina/administração & dosagem , Hematínicos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Anemia/etiologia , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Quimioterapia Combinada , Epoetina alfa , Eritropoetina/efeitos adversos , Feminino , Hematínicos/efeitos adversos , Hemoglobinas , Hepatite C Crônica/complicações , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Ribavirina/administração & dosagem , Ribavirina/efeitos adversosRESUMO
BACKGROUND/AIMS: Questions remain regarding the etiology of steatosis in hepatitis C, and its impact on disease progression and treatment outcomes. METHODS: We evaluated liver biopsies from 574 patients with chronic hepatitis C from a single center. RESULTS: Severity of steatosis was associated with body mass index, HCV genotype 3 infection, age, and duration of infection (P=0.01). Serum HCV RNA levels were associated with severity of steatosis in HCV genotype 3 infection (P=0.03). In HCV genotype 1 infection, fibrosis was associated with severity of steatosis (P<0.01), and patients who achieved SVR had lesser degrees of pre-treatment steatosis compared to nonresponders (4.6+/-1.6 vs. 10.1+/-1.1%, P=0.02). Genotype 1 infected patients with an early virologic response were more likely to have grade 0 steatosis compared to those without an early response (71 vs. 42%; P=0.003). Evaluation of paired biopsies demonstrated a marked decline in steatosis in genotype 3 patients who achieved SVR (P<0.01). CONCLUSIONS: In conclusion, steatosis is an important cofactor in hepatitis C as it is associated with fibrosis and reduces the likelihood of achieving early and sustained virologic response in genotype 1 infected patients.
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Antivirais/uso terapêutico , Fígado Gorduroso/virologia , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Adulto , Biópsia , Índice de Massa Corporal , Estudos de Coortes , Progressão da Doença , Fígado Gorduroso/patologia , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Combination therapy with interferon alpha (IFN-alpha) and ribavirin (RBV) or pegylated IFN-alpha (PEG-IFN-alpha)/RBV for chronic hepatitis C virus (HCV) infection often causes anemia, prompting RBV dose reduction/discontinuation. This study assessed whether epoetin alfa could maintain RBV dose, improve quality of life (QOL), and increase hemoglobin (Hb) in anemic HCV-infected patients. METHODS: HCV-infected patients (n = 185) on combination therapy who developed anemia (Hb < or = 12 g/dL) were randomized into a U. S. multicenter, placebo-controlled, clinical trial of epoetin alfa, 40,000 U subcutaneously, once weekly vs. matching placebo. The study design used an 8-week, double-blind phase (DBP) followed by an 8-week, open-label phase (OLP), in which placebo patients were crossed over to epoetin alfa. RESULTS: At the end of the DBP, RBV doses were maintained in 88% of patients receiving epoetin alfa vs. 60% of patients receiving placebo (P < 0.001). Mean QOL scores at the end of the DBP improved significantly on all domains of the Linear Analog Scale Assessment (LASA) and on 7 of the 8 domains of the Short Form-36, version 2 (SF-36v2). Mean Hb increased by 2.2 +/- 1.3 g/dL (epoetin alfa) and by 0.1 +/- 1.0 g/dL (placebo) in the DBP (P < 0.001). Similar results were demonstrated in patients who switched from placebo to epoetin alfa in the OLP. Epoetin alfa was well tolerated; the most common adverse effects were headache and nausea. CONCLUSIONS: Epoetin alfa maintained RBV dose and improved QOL and Hb in anemic HCV-infected patients receiving combination therapy.
Assuntos
Antivirais/administração & dosagem , Eritropoetina/uso terapêutico , Hematínicos/uso terapêutico , Hepatite C/tratamento farmacológico , Ribavirina/administração & dosagem , Adulto , Idoso , Anemia/induzido quimicamente , Anemia/tratamento farmacológico , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada , Epoetina alfa , Eritropoetina/efeitos adversos , Feminino , Hematínicos/efeitos adversos , Hemoglobinas/metabolismo , Hepatite C/fisiopatologia , Humanos , Interferon-alfa/uso terapêutico , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Proteínas Recombinantes , Ribavirina/efeitos adversos , Carga ViralRESUMO
Recombinant human interleukin 12 (IL-12) is an immunomodulatory cytokine that is active against several viruses. Treatment options in patients with chronic hepatitis C with nonresponse to interferon (IFN)-based therapy are limited. Prior dose-ranging studies have indicated drug tolerability and transient suppression of hepatitis C virus (HCV) RNA by IL-12. The aim of this study was to determine the safety and efficacy of prolonged IL-12 therapy in patients who have failed treatment with IFN-alpha +/- ribavirin. A total of 225 patients at 21 U.S. sites who had a history of nonresponse to IFN-alpha or combination IFN-alpha plus ribavirin for treatment of HCV were randomized to 500 ng/kg IL-12 or placebo subcutaneously twice weekly for 12 weeks. The groups were then unblinded; patients receiving IL-12 continued for another 36 weeks, and the placebo group received 48 weeks of treatment with IL-12 in an open-label fashion. HCV RNA, serum alanine aminotransferase (ALT) level, and a repeat liver biopsy were assessed at 24 weeks following therapy. Approximately 1% (2 of 160) of nonresponsive patients enrolled for treatment had a sustained virologic response to IL-12 therapy, but 3% (7 of 225) developed severe adverse events probably related to treatment, resulting in early termination of the trial. Common adverse effects reported by most patients included chills, fever, fatigue, headache, and arthralgia. At termination of the study, 160 patients had received at least 8 weeks of treatment with IL-12. Paired liver biopsy specimens were available for evaluation in 54 patients, but there were no significant changes in Knodell fibrosis or histologic activity index (HAI) scores. In conclusion, IL-12 as monotherapy at the doses used in this trial for chronic hepatitis C has low efficacy, was poorly tolerated, and is unlikely to provide an alternative to conventional IFN-based therapy.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interleucina-12/uso terapêutico , Adjuvantes Imunológicos/efeitos adversos , Adulto , Alanina Transaminase/sangue , Método Duplo-Cego , Feminino , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interleucina-12/efeitos adversos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Retratamento , Falha de TratamentoRESUMO
BACKGROUND AND AIM: Hyaluronic acid (HA) is a glycosaminoglycan synthesized by hepatic stellate cells that has been shown to correlate with liver fibrosis in chronic hepatitis C (HCV) patients. However, its use in monitoring fibrosis over time has not been established. The aim of the present study was to assess the serial relationships between HA and liver fibrosis before and after treatment. METHODS: Seventy-six previously untreated chronic HCV patients received interferon-based therapy over 48 weeks. Serum HA levels were measured and liver biopsies were obtained at baseline, and 24 weeks post-treatment. Histological fibrosis was assessed by using the Knodell and METAVIR scoring systems. RESULTS: Knodell fibrosis was evaluated in 76 patients; METAVIR fibrosis in 72 patients. Following treatment, patients were grouped into those with increased fibrosis (Knodell = 17; METAVIR = 16), no change (Knodell = 50; METAVIR = 45), or decreased fibrosis (Knodell = 9; METAVIR = 11), relative to baseline. Moderate correlations between HA and fibrosis scores were found before treatment (Knodell R = 0.45; METAVIR R = 0.40) and post-treatment (Knodell R = 0.45; METAVIR R = 0.61). However, changes in HA correlated poorly with changes in fibrosis scores over the study period (Knodell R = 0.11; METAVIR R = 0.06). There was poor qualitative agreement between the direction of HA change and the direction of change in fibrosis scores (Knodell kappa = 0.04; METAVIR kappa = 0.08). The sustained virological response group (n = 18) had a significantly decreased mean HA compared with non-responders (-27.9 vs 21.7 micro g/L; P = 0.009), but pretreatment HA did not predict a response. CONCLUSIONS: Serum HA showed a modest association with hepatic fibrosis, and remains a useful non-invasive marker. However, serum HA alone has limited value in predicting histological changes over a treatment period.