RESUMO
BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.
Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Uridina Monofosfato/análogos & derivados , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Porto Rico , Proteínas Recombinantes/administração & dosagem , Sofosbuvir , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/administração & dosagemRESUMO
BACKGROUND & AIMS: Sofosbuvir (formerly GS-7977) is a pyrimidine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase. We assessed the safety, tolerability, antiviral activity, and pharmacokinetics of sofosbuvir plus pegylated-interferon (PegIFN)/ribavirin (RBV) in a 28-day, dose-ranging trial in treatment-naïve patients infected with genotype 1 HCV. METHODS: In this double-blind study, 64 patients were randomized (1:1:1:1) to receive one of three once-daily doses of oral sofosbuvir (100, 200, or 400mg) or placebo plus PegIFN/RBV for 28 days, after which all patients continued to receive PegIFN/RBV alone for a further 44 weeks. RESULTS: Patients in the sofosbuvir/PegIFN/RBV groups experienced mean reductions in HCV RNA >5 log10 IU/ml (-5.3 for 100 mg, -5.1 for 200 mg and -5.3 for 400 mg) vs. -2.8 log10 IU/ml for placebo/PegIFN/RBV after 28 days. Rapid virologic response (RVR) rates were markedly higher after sofosbuvir treatment (88-94%) than placebo (21%), as were rates of sustained virologic response (SVR) at post-treatment Week 24 (56%, 83%, and 80% for sofosbuvir 100, 200, and 400 mg, respectively, vs. 43% for placebo). The number of patients experiencing virologic breakthrough and post-treatment relapse was higher in the sofosbuvir 100 mg group than sofosbuvir 200 and 400 mg groups. Sofosbuvir was well tolerated; the most frequent adverse events were fatigue and nausea. CONCLUSIONS: These results support further studies with sofosbuvir at 200 mg and 400 mg to determine the optimal dose and treatment duration of sofosbuvir in HCV genotype 1.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Uridina Monofosfato/análogos & derivados , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hepacivirus/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Sofosbuvir , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/farmacocinética , Adulto JovemRESUMO
We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t(1/2)) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (C(max)) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of -1.95 log(10) IU/ml was obtained for 400 mg GS-9851, compared with -0.090 log(10) IU/ml for the placebo. Most patients had a decrease in HCV RNA of ≥1.0 log(10) IU/ml after 3 days' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.
Assuntos
Antivirais/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Nucleotídeos/farmacocinética , RNA Viral/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/sangue , Antivirais/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Meia-Vida , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/sangue , Nucleotídeos/farmacologia , Placebos , RNA Viral/biossíntese , Carga Viral/efeitos dos fármacosRESUMO
OBJECTIVE: To examine imatinib mesylate's effects on stellate cell responses in vivo and in vitro. The hepatic stellate cell (HSC) is a key target of anti-fibrotic therapies. Imatinib mesylate is a small molecule receptor tyrosine kinase inhibitor indicated for treatment of chronic myelogenous leukaemia and GI stromal tumours. DESIGN: Because imatinib inhibits ß-PDGFR signalling, which stimulates HSC proliferation, we assessed its activity in culture and in vivo, and examined downstream targets in a human stellate cell line (LX-2) using cDNA microarray. METHODS AND RESULTS: Imatinib inhibited proliferation of LX-2 cells (0.5-10 mM) but not primary human stellate cells, with no effect on viability, associated with attenuated ß-PDGFR phosphorylation. Mitochondrial activity and superoxide anion production were decreased in response to imatinib. cDNA microarray uncovered up-regulation of 29 genes in response to imatinib, including interleukin-6 (IL-6) mRNA, which was correlated with progressive IL-6 secretion. Imatinib also decreased gene expression of collagen α(1) (I), alpha smooth muscle actin, ß-PDGFR, transforming growth factor ß receptor type 1, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2. In vivo, imatinib administered to rats beginning 4 weeks after starting thioacetamide (TAA) led to reduced collagen content, with significant reductions in portal pressure and down-regulation of fibrogenic genes in whole liver. Importantly, hepatic IL-6 mRNA levels were significantly increased in TAA-treated animals receiving imatinib. CONCLUSIONS: These findings reinforce the anti-fibrotic activity of imatinib and uncover an unexpected link between inhibition of HSC activation by imatinib and enhanced secretion of IL-6, a regenerative cytokine.
Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Interleucina-6/metabolismo , Cirrose Hepática Experimental/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Benzamidas , Biomarcadores/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica/métodos , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/patologia , Humanos , Mesilato de Imatinib , Interleucina-6/genética , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/enzimologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Tioacetamida , Fatores de Tempo , Regulação para CimaRESUMO
BACKGROUND & AIMS: The GLOBE trial has compared the efficacy and safety of telbivudine versus lamivudine treatment over 2 years in patients with chronic hepatitis B. METHODS: Hepatitis B e antigen (HBeAg)-positive (n = 921) and HBeAg-negative (n = 446) patients received telbivudine or lamivudine once daily for 104 weeks. The primary outcome, assessed in the intent-to-treat population, was therapeutic response (hepatitis B virus DNA <5 log(10) copies/mL and either HBeAg loss or normalization of alanine aminotransferase [ALT] level). RESULTS: The therapeutic response to telbivudine was superior to that of lamivudine in HBeAg-positive (63% vs 48%; P < .001) and HBeAg-negative (78% vs 66%; P = .007) patients. HBeAg-positive patients given telbivudine also had better outcomes compared with lamivudine in terms of nondetectable viremia (< 300 copies/mL) at 55.6% versus 38.5% (P < .001), HBeAg loss at 35.2% versus 29.2% (P = .056), and viral resistance at 25.1% versus 39.5% (P < .001). Hepatitis B e antigen seroconversion was 29.6% versus 24.7% (P = .095) in all patients and 36% versus 27% (P = .022) in patients with baseline ALT level > or = 2 times normal. Telbivudine-treated HBeAg-negative patients showed higher rates of nondetectable viremia compared with lamivudine at 82.0% versus 56.7% (P < .001) and less resistance at 10.8% versus 25.9% (P < .001). Adverse events occurred with similar frequency, whereas grade 3/4 increases in creatine kinase levels were more common in patients given telbivudine (12.9% vs 4.1%, P < .001). Multivariate logistic regression analyses identified telbivudine treatment, among other variables, as an independent predictor of better week 104 outcomes. CONCLUSIONS: Telbivudine is superior to lamivudine in treating patients with chronic hepatitis B over a 2-year period.
Assuntos
Antivirais/uso terapêutico , Saúde Global , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Nucleosídeos/uso terapêutico , Pirimidinonas/uso terapêutico , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/efeitos adversos , Antivirais/farmacologia , DNA Viral/efeitos dos fármacos , Método Duplo-Cego , Feminino , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Humanos , Lamivudina/efeitos adversos , Lamivudina/farmacologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nucleosídeos/efeitos adversos , Nucleosídeos/farmacologia , Estudos Prospectivos , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacologia , Análise de Regressão , Telbivudina , Timidina/análogos & derivados , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
Chronic hepatitis C (HCV) infection leads to the development of hepatic fibrosis. No single test for diagnosing liver fibrosis is completely optimal. The ability to assess the extent and progression of fibrosis is important in the clinical setting, especially in the context of current treatments and therapeutic trials. More accurate and noninvasive methods to diagnose and monitor fibrosis are needed, because these trials will require serial evaluations of liver fibrosis to assess a compound's antifibrotic effect.
Assuntos
Hepacivirus/isolamento & purificação , Hepatite C Crônica/diagnóstico , Cirrose Hepática/diagnóstico , Biópsia/métodos , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/virologia , UltrassonografiaRESUMO
BACKGROUND: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. METHODS: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 µg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. FINDINGS: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. INTERPRETATION: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. FUNDING: Gilead Sciences.
Assuntos
Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Genótipo , Cefaleia/induzido quimicamente , Hepacivirus/classificação , Hepacivirus/patogenicidade , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/administração & dosagem , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Polietilenoglicóis/administração & dosagem , RNA Viral/análise , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Ribavirina/administração & dosagem , Prevenção Secundária , Sofosbuvir , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/uso terapêutico , Adulto JovemRESUMO
We have evaluated the possible mechanisms of liver fibrosis caused by Fasciola hepatica in an animal model and in culture using immortalized human stellate cells. Liver biopsies of F. hepatica-infected rats were performed at wk 8 and 16. Serum-starved LX-2 cells, a human stellate cell line, were exposed to increasing concentrations of Fas2 antigen. The expression of key fibrosis-related genes was evaluated by qRT-PCR. There was a significant correlation between fibrogenic gene expression and both intensity and duration of infection. LX-2 cells exposed to Fas2 showed progressively increased expression of mRNAs for Collagen I, alpha-smooth muscle-actin, platelet-derived growth factor beta receptor, and tissue inhibitor of metalloproteinase II; inhibition of Fas2 cysteine proteinase activity by E-64 abrogated these increases, suggesting that the protease activity of Fas2 is involved in fibrogenic stimulation. In summary, F. hepatica infection is associated with up-regulation of mRNAs associated with hepatic fibrogenesis in vivo and in activated hepatic stellate cells.
Assuntos
Antígenos de Helmintos/metabolismo , Cisteína Endopeptidases/metabolismo , Fasciola hepatica/enzimologia , Fasciolíase/complicações , Células Estreladas do Fígado/fisiologia , Cirrose Hepática/etiologia , Actinas/genética , Análise de Variância , Animais , Linhagem Celular , Colágeno/genética , Modelos Animais de Doenças , Fasciola hepatica/patogenicidade , Fasciolíase/patologia , Expressão Gênica , Humanos , Cirrose Hepática/patologia , Masculino , Ratos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Inibidor Tecidual de Metaloproteinase-2/genéticaRESUMO
Hepatic fibrosis is the scarring response of the liver to chronic liver injury; when fibrosis progresses to cirrhosis, morbid complications can develop. Available therapies for many chronic liver diseases are ineffective, with liver transplantation as the only option, though the supply of donor organs is inadequate to meet the growing demand. Novel approaches that attack the scarring response are therefore urgently needed. Optimism in this effort is fueled by major insights into the pathogenesis of fibrosis and by accumulating evidence that even cirrhosis is reversible in many patients. Most evolving antifibrotic therapies will be aimed at inhibiting the activated hepatic stellate cell, which is responsible for the fibrotic response to injury. This review describes the ways in which insights into the cellular basis of hepatic fibrosis are leading to realistic strategies for antifibrotic treatment that may revolutionize the management of patients with chronic liver disease.
Assuntos
Cirrose Hepática/terapia , Humanos , Fígado/citologia , Cirrose Hepática/etiologia , Cirrose Hepática/fisiopatologiaRESUMO
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) undergo activation during the development of liver fibrosis. Transcriptional regulation plays a key role in this process. We studied the role of transcription factor myocyte enhancer factor 2 (MEF2) during HSC activation. METHODS: Culture of HSCs isolated from rat liver on plastic dishes and HSC-T6 on a basement membrane-like matrix were used as models of HSC activation and deactivation, respectively. The expression and activity of MEF2 were correlated with HSC activation. The roles of MEF2 during HSC activation were assessed in vitro and in vivo by animal models of fibrosis. RESULTS: Early induction of MEF2 messenger RNA and protein accompanied culture-induced HSC activation. This was associated with enhanced MEF2 DNA binding and transactivation activity. p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase pathway was required for increased MEF2 activity during HSC activation. Increased MEF2 protein also correlated with fibrosis in vivo. Reversal of HSC activation was paralleled by a marked decrease in MEF2 protein and activity. Functionally, enhancing MEF2 significantly increased the expression of alpha-smooth muscle actin (alpha-SMA), activated collagen I promoter activity, and stimulated HSC proliferation. MEF2 interference RNA significantly inhibited expression of alpha-SMA, collagen alpha1(I), and proliferating cell nuclear antigen. CONCLUSIONS: The studies provide the first evidence for the presence of MEF2 in the liver and show that MEF2 regulates multiple aspects of HSC activation. These studies show a novel role of MEF2 as a key nuclear mediator that may participate in the pathologic process of liver fibrogenesis in vivo.