RESUMO
UNLABELLED: Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 ?g weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. RESULTS: In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants. CONCLUSION: Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.
Assuntos
Antivirais/uso terapêutico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Rejeição de Enxerto/prevenção & controle , Hepacivirus/genética , Hepatite C Crônica , Humanos , Imunossupressores/uso terapêutico , Interferons/uso terapêutico , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Ribavirina/uso terapêutico , Resposta Viral Sustentada , Tacrolimo/uso terapêutico , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND & AIMS: Hepatic venous pressure gradient (HVPG) is associated with a risk of liver events in patients with chronic hepatitis C. Antiviral therapies that lead to a sustained virologic response (SVR) reduce portal pressure and prevent liver disease progression. However, it is not clear to what extent the progression of hepatitis C is modified once patients develop cirrhosis with severe portal hypertension (CSPH) (HVPG ≥ 10 mm Hg). We assessed the effects of HVPG and SVR on the risk of liver decompensation, hepatocellular carcinoma, and/or death in patients with hepatitis C-related cirrhosis. METHODS: We collected data from 100 patients with hepatitis C and compensated cirrhosis who underwent HVPG measurement 3 months or less before (baseline) and 24 weeks after therapy with pegylated interferon alfa-2a and ribavirin at 4 hospitals in Spain, from 2001 through 2009. SVR was defined as undetectable serum HCV RNA level 24 weeks after treatment ended. Clinical data were collected until death, liver transplantation, or December 2012 (median, 5 y; interquartile range, 1.4-7 y). RESULTS: Seventy-four patients had CSPH at baseline and 35% of patients achieved an SVR. During the follow-up period, 19 patients developed liver decompensation (ascites, variceal bleeding, or encephalopathy). The actuarial probability values for liver decompensation at 1, 5, and 7 years were 3%, 19% and 22%, respectively. The baseline level of HVPG, but not SVR, was associated independently with the risk of liver decompensation. CONCLUSIONS: Patients with CSPH, regardless of an SVR to therapy for hepatitis C, remain at risk for liver decompensation within the first 5 years after treatment; they should be monitored closely.
Assuntos
Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Hipertensão Portal/complicações , Hipertensão Portal/patologia , Falência Hepática/epidemiologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/mortalidade , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/mortalidade , Humanos , Hipertensão Portal/mortalidade , Interferon-alfa/uso terapêutico , Falência Hepática/complicações , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Medição de Risco , Espanha , Análise de Sobrevida , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND & AIMS: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy. METHODS: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group). RESULTS: Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6-53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir. CONCLUSIONS: In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Ribavirina/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antivirais/efeitos adversos , Ásia , Biomarcadores/sangue , Método Duplo-Cego , Quimioterapia Combinada , Europa (Continente) , Feminino , Hepacivirus/enzimologia , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C/sangue , Hepatite C/diagnóstico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , América do Norte , Polietilenoglicóis/efeitos adversos , Inibidores de Proteases/efeitos adversos , RNA Viral/sangue , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Recidiva , Ribavirina/efeitos adversos , Simeprevir , Sulfonamidas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Adulto JovemRESUMO
BACKGROUND & AIMS: The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection. METHODS: Prospective, multicentre, national registry that includes naïve and treatment-experienced patients with HCV genotype 1 infection, who had bridging fibrosis or cirrhosis and were treated with triple therapy (peginterferon alfa-2a or alfa-2b, ribavirin and boceprevir) as compassionate use, and in accordance with the Summary of Product Characteristics. RESULTS: Most of the patients (68.2%) were male, with a mean age of 53 years, 75% (n = 128) had HCV 1b genotype and baseline viral load of 6.2 log. According to prior treatment, 20% of patients were treatment-naïve and 80% had received prior treatment. Approximately 36.5% of patients (n = 62) reported at least one serious adverse events (SAEs) (total SAEs = 103). The most common SAEs were neutropenia (57.6%), anaemia (47.6%) and grade 3 thrombopenia (25.9%). Patients with albumin <3.5 g/dl and bilirubin >2 mg/dl had an increased relative risk (greater than one-fold) for SAEs, including infections and hepatic decompensation. In the intent-to-treat analysis (n = 170), the overall percentage of patients with SVRw12 was 46.5%. In patients with 1 log decrease at week 4 (lead-in phase), the overall SVRw12 rate was 67.0%. In the patients initiating triple therapy with boceprevir (n = 139), the global response rate was 56.4%. In a multivariate analysis, an increased probability of achieving SVR was associated with response to prior treatment (relapsers), >1 log decrease in viral load in the lead-in phase and baseline albumin >3.5 g/dl. CONCLUSIONS: Triple therapy in patients with severe fibrosis/cirrhosis is associated with a higher rate of SAE and a lower rate in comparison with patients with mild disease. However, for patients with intact liver function, it could be considered as a treatment option, when other alternatives would not be available.
Assuntos
Hepacivirus/genética , Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Inibidores de Proteases/uso terapêutico , Ribavirina/uso terapêutico , Ensaios de Uso Compassivo , Quimioterapia Combinada/efeitos adversos , Hepatite C/complicações , Hepatite C/genética , Humanos , Interferon-alfa/efeitos adversos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Prolina/efeitos adversos , Prolina/uso terapêutico , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Ribavirina/efeitos adversos , EspanhaRESUMO
BACKGROUND: Hepatitis C virus (HCV) is associated with a higher prevalence of steatosis compared to the general population. AIM: Our aim was to assess the impact of PNPLA3 rs738409 G-allele on steatosis in HCV patients. MATERIAL AND METHODS: We included 474 HCV patients treated with peginterferon plus ribavirin. PNPLA3 rs738409 was genotyped and patients were classified according to alleles and genotypes. Steatosis was detected in 46.4% (220/474). Fibrosis was assessed by Scheuer score. Gene expression was analyzed in Huh7.5 and Huh7 cells using Real Time-PCR. RESULTS: PNPLA3 allele-G was associated with steatosis [54.1% (126/233) vs. 39% (94/241)] (p = 0.0001). In HCV-1, allele-G was related to steatosis [50.6% (82/162) vs. 32.3% (53/164)] (p = 0.001), but did not in HCV-3 [61.9% (26/42) vs. 62% (31/50)] (p = 0.993). PNPLA3 allele-G was associated with steatosis in patients with IL28B-CT/TT [57.7% (82/142) vs. 37.1% (56/151)] (p = 0.0001), but did not in IL28B-CC [47.8% (43/90) vs. 42% (37/88)] (p = 0.442). Independent variables associated with steatosis were: PNPLA3 G-allele [O.R. 1.84 (CI95%: 1.06-3.21); p = 0.007], age [O.R. 1.04 (CI95%: 1.01-1.07); p = 0.017], HCV-genotype 3 [O.R. 2.46 (CI95%: 1.30-4.65); p = 0.006], HOMA > 4 [O.R. 2.72 (CI95%: 1.27-5.82); p = 0.010]. Since PNPLA3 RNA could not be detected on PBMC from HCV patients, an in vitro analysis was performed. Huh7.5 cells infected with JFH1 had a decreased PNPLA3 gene expression (fold inhibition = 3.2 ± 0.2), while Huh7 cells presented increased PNPLA3 gene expression (fold induction = 1.5 ± 0.2). CONCLUSION: PNPLA3 allele-G modulated the development of steatosis, particularly in patients with HCV-1 and IL28B-CT/TT genotype, but was not associated with SVR. Metabolic but not viral steatosis seems to be PNPLA3 regulated. Gene interaction may result in differential PNPLA3 gene expression levels in HCV infection.
Assuntos
Fígado Gorduroso/genética , Hepacivirus/genética , Hepatite C Crônica/genética , Interleucinas/genética , Lipase/genética , Fígado/patologia , Proteínas de Membrana/genética , RNA Viral/genética , Adulto , Antivirais/uso terapêutico , Células Cultivadas , Estudos de Coortes , Estudos Transversais , Quimioterapia Combinada , Fígado Gorduroso/virologia , Feminino , Perfilação da Expressão Gênica , Genótipo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Interferons , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Fatores de Risco , Carga ViralRESUMO
The introduction of telaprevir in the therapeutic armamentarium for hepatitis C virus infection is a major advance, even in patients unresponsive to prior treatment with interferon and ribavirin. In this group of patients, sustained viral response is achieved in more than 80% of those with recurrence and who received triple therapy. In partial responders, more than half achieve cure with the triple combination of pegylated interferon, ribavirin and telaprevir. Unfortunately, the results are less good in null responders, especially given that many are of a certain age and have advanced fibrosis. Patients in this group should be carefully selected to identify those most likely to derive a benefit from triple therapy.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Inibidores de Proteases/uso terapêutico , Antivirais/administração & dosagem , Ensaios Clínicos como Assunto , Farmacorresistência Viral , Quimioterapia Combinada , Seguimentos , Hepatite C Crônica/complicações , Humanos , Interferons/administração & dosagem , Interferons/uso terapêutico , Cirrose Hepática/etiologia , Estudos Multicêntricos como Assunto , Oligopeptídeos/administração & dosagem , Seleção de Pacientes , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Inibidores de Proteases/administração & dosagem , Recidiva , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
Since the discovery of the hepatitis C virus (HCV), a plethora of experimental models have evolved, allowing the virus's life cycle and the pathogenesis of associated liver diseases to be investigated. These models range from inoculation of cultured cells with serum from patients with hepatitis C to the use of surrogate models for the study of specific stages of the HCV life cycle: retroviral pseudoparticles for the study of HCV entry, replicons for the study of HCV replication, and the HCV cell culture model, which reproduces the entire life cycle (replication and production of infectious particles). The use of these tools has been and remains crucial to identify potential therapeutic targets in the different stages of the virus's life cycle and to screen new antiviral drugs. A clear example is the recent approval of two viral protease inhibitors (boceprevir and telaprevir) in combination with pegylated interferon and ribavirin for the treatment of chronic hepatitis C. This review analyzes the advances made in the molecular biology of HCV and highlights possible candidates as therapeutic targets for the treatment of HCV infection.
Assuntos
Hepacivirus/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Ensaios Clínicos Fase I como Assunto , Farmacorresistência Viral , Quimioterapia Combinada , Genoma Viral , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepacivirus/fisiologia , Hepacivirus/ultraestrutura , Hepatite C/virologia , Humanos , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Terapia de Alvo Molecular , Polietilenoglicóis/uso terapêutico , RNA Viral/genética , Receptores Virais/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Proteínas Virais/fisiologia , Cultura de Vírus/métodos , Replicação ViralRESUMO
OBJECTIVE: Insulin resistance is a predictor of poor response to peginterferon/ribavirin in patients infected with the chronic hepatitis C virus (HCV). There are no data on direct-acting antivirals. This exploratory analysis assessed the effect of metabolic factors and insulin resistance, measured by homoeostatic model assessment (HOMA), on virological response to telaprevir in Study C208. DESIGN: Overall, 161 HCV genotype 1-infected, treatment-naïve patients received 12 weeks of telaprevir plus peginterferon/ribavirin, then 12/36 weeks of peginterferon/ribavirin depending on on-treatment response criteria. The prognostic significance of several factors, including HOMA-insulin resistance (HOMA-IR), on virological response at weeks 4 and 12, end of treatment and 24 weeks after treatment was explored by multiple regression analysis. RESULTS: Baseline HOMA-IR data were available for 147 patients; baseline characteristics were consistent with the overall population. Baseline HOMA-IR <2, 2-4 and >4 was seen in 54%, 30% and 16% of patients, respectively. Neither response rates (any time point) nor week 4 viral load decline were significantly influenced by baseline HOMA-IR. In multivariate analyses, fibrosis stage and low-density lipoprotein cholesterol level were predictive of sustained virological response (OR 0.47 and 1.02, respectively). After the end of treatment, HOMA-IR was significantly lower in patients with sustained virological response than in those without (0.61 vs 1.34 for relapsers and 1.15 for non-responders; p<0.05). CONCLUSION: In this study, baseline HOMA-IR was not predictive of virological response to telaprevir in HCV genotype 1-infected, treatment-naïve patients, while sustained virological response was associated with improved HOMA-IR. These results suggest that metabolic factors and insulin resistance do not have a significant effect on telaprevir-based treatment efficacy.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Resistência à Insulina , Interferon-alfa/uso terapêutico , Oligopeptídeos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adolescente , Adulto , Idoso , DNA Viral/análise , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C Crônica/metabolismo , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND & AIMS: Recent studies have shown that 12 weeks of treatment with telaprevir, administered every 8 hours (q8h), combined with pegylated interferon (peginterferon) alfa-2a plus ribavirin significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype 1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12 h) in combination with peginterferon alfa-2a or alfa-2b. METHODS: Treatment-naive patients (n = 161) infected with HCV genotype 1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8 h or 1125 mg q12 h) in combination with standard doses of peginterferon alfa-2a (180 µg/wk) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 µg·kg(-1)·wk(-1)) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of treatment with peginterferon alfa and ribavirin, based on virologic response. RESULTS: Baseline characteristics were similar for all groups. SVR rates were 81.0% to 85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P ≥ .787), between the pooled q8 h and q12 h groups (P = .997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = .906). The safety profile was similar among all groups. CONCLUSIONS: A high proportion (>80%) of patients achieved an SVR regardless of the telaprevir dosing frequency (q8 h or q12 h) or type of peginterferon alfa used (alfa-2a or alfa-2b).
Assuntos
Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Oligopeptídeos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/farmacocinética , RNA Viral/análise , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS: Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS: Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS: SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.
Assuntos
Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Antivirais/uso terapêutico , Estudos de Coortes , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/genética , Humanos , Análise de Intenção de Tratamento , Interferon alfa-2 , Cirrose Hepática/complicações , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteínas Recombinantes , Estudos Retrospectivos , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND/AIMS: Recurrence of hepatitis C after liver transplantation (LT) is universal and may cause premature graft loss. We evaluated the efficacy and safety of antiviral therapy in HCV-infected patients with decompensated cirrhosis awaiting LT. METHODS: Fifty-one patients underwent treatment with peginterferon-alfa-2a and ribavirin. A control group of 51 untreated individuals awaiting LT were matched by age, Child-Pugh and MELD scores and time on the waiting list. RESULTS: Case and control patients were comparable for all relevant variables. Fifteen treated patients (29%) had undetectable HCV-RNA at the time of transplantation and 10 (20%) achieved SVR. Early virological response and non-1 genotype were the strongest predictors of viral clearance. There was a higher incidence of bacterial infections in treated patients vs controls, particularly in Child-Pugh B-C individuals (17 vs 3 episodes) (log-rank=0.0016). Importantly, the incidence of spontaneous bacterial peritonitis (SBP) in patients who were not receiving norfloxacin prophylaxis (n=83) was significantly higher in the treated group than in controls (log-rank=0.01). CONCLUSIONS: Our data demonstrate that antiviral treatment prevents hepatitis C recurrence in 20% of HCV-infected patients. However, treatment should be recommended with caution in individuals with poor liver function who do not receive norfloxacin prophylaxis for SBP, since it increases the risk of bacterial infections.
Assuntos
Antivirais/efeitos adversos , Infecções Bacterianas/epidemiologia , Hepatite C/tratamento farmacológico , Transplante de Fígado , Adulto , Idoso , Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Feminino , Hepatite C/complicações , Humanos , Incidência , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Peritonite/epidemiologia , Peritonite/microbiologia , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/microbiologia , Proteínas Recombinantes , Recidiva , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Segurança , Fatores de Tempo , Carga Viral , Listas de Espera , Adulto JovemAssuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Interferon Tipo I/uso terapêutico , Polietilenoglicóis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Antivirais/administração & dosagem , Biópsia , Contraindicações , Diagnóstico por Imagem/métodos , Quimioterapia Combinada , Genótipo , Acessibilidade aos Serviços de Saúde , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Consentimento Livre e Esclarecido , Interferon Tipo I/administração & dosagem , Interferons , Interleucinas/genética , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Equipe de Assistência ao Paciente , Polietilenoglicóis/administração & dosagem , Prolina/administração & dosagem , Prolina/análogos & derivados , Prolina/uso terapêutico , Inibidores de Proteases/administração & dosagem , Recidiva , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Carga ViralRESUMO
UNLABELLED: Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.
Assuntos
Antivirais/uso terapêutico , Desoxicitidina/análogos & derivados , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Oligopeptídeos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prolina/análogos & derivados , Ribavirina/uso terapêutico , Adulto , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/sangue , Antimetabólitos/uso terapêutico , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/métodos , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Inibidores de Proteases/uso terapêutico , RNA Viral/antagonistas & inibidores , RNA Viral/genética , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoAssuntos
Hepatite C/complicações , Hepatite C/tratamento farmacológico , Cirrose Hepática/complicações , Antivirais/uso terapêutico , Progressão da Doença , Infecções por HIV/complicações , Hepatite C/cirurgia , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Transplante de Fígado , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes , Recidiva , Reprodutibilidade dos Testes , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications.
Assuntos
Anemia Aplástica/induzido quimicamente , Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Interferons/efeitos adversos , Oligopeptídeos/efeitos adversos , Pancitopenia/induzido quimicamente , Polietilenoglicóis/efeitos adversos , Ribavirina/efeitos adversos , Idoso , Anemia Aplástica/sangue , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Biópsia , Exame de Medula Óssea , Quimioterapia Combinada , Evolução Fatal , Feminino , Hepatite C Crônica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Pancitopenia/sangue , Pancitopenia/diagnóstico , Pancitopenia/terapia , Fatores de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To carry out a systematic review of the risk factors for, and incidence of, major depressive episode (MDE) related to antiviral therapy for chronic hepatitis C. DATA SOURCES: The MEDLINE, PsycINFO, and Cochrane databases were searched to locate articles published from the earliest available online year until June 2011 using the keywords hepatitis C, interferon-alpha, peginterferon, pegylated interferon, depression, and mood and Boolean operators. Articles written in English, Spanish, and French were included. STUDY SELECTION: Prospective studies reporting incidence of interferon-alpha-induced MDE were included. At baseline, patients did not present a DSM-IV/ICD depressive episode, and evaluation was performed by a trained clinician. Twenty-six observational studies met the inclusion criteria. DATA EXTRACTION: Extracted data included authors, year of publication, design, characteristics of the population, viral coinfection, adjunctive psychopharmacology, instruments to assess depression, dose and type of interferon-alpha, adjunctive ribavirin treatment, and follow-up time. Outcome of incidence of MDE (primary outcome measure) was abstracted, as were potential predictive variables. DATA SYNTHESIS: A full review was performed. Meta-analysis of the cumulative incidence of induced MDE as a function of time was carried out. Odds ratios (ORs) and mean differences were used to estimate the strength of association of variables. RESULTS: Overall cumulative incidence of depression was 0.25 (95% CI, 0.16 to 0.35) and 0.28 (95% CI, 0.17 to 0.42) at 24 and 48 weeks of treatment, respectively. According to our analysis, high baseline levels of interleukin 6 (mean difference = 1.81; 95% CI, 1.09 to 2.52), female gender (OR = 1.40; 95% CI, 1.02 to 1.91), history of MDE (OR = 3.96; 95% CI, 2.52 to 6.21), history of psychiatric disorder (OR = 3.18; 95% CI, 1.60 to 6.32), subthreshold depressive symptoms (mean difference = 0.96; 95% CI, 0.31 to 1.61), and low educational level (mean difference = -0.99; 95% CI, -1.59 to -0.39) were predictive variables of MDE during antiviral treatment. CONCLUSIONS: One in 4 chronic hepatitis C patients who start interferon and ribavirin treatment will develop an induced major depressive episode. Clinicians should attempt a full evaluation of patients before starting antiviral treatment in order to identify those at risk of developing interferon-induced depression.
Assuntos
Antivirais/efeitos adversos , Transtorno Depressivo Maior/induzido quimicamente , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Antivirais/uso terapêutico , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Feminino , Hepatite C Crônica/epidemiologia , Humanos , Incidência , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Recurrence of hepatitis C virus (HCV) infection is a relevant problem of liver transplantation programs. We evaluated the effect of antiviral therapy on disease progression in 81 HCV-infected liver transplantation recipients. METHODS: Patients with mild hepatitis C recurrence (fibrosis stage F0 to F2, n = 54) were randomized to no treatment (group A, n = 27) or peginterferon alfa-2b/ribavirin for 48 weeks (group B, n = 27). Patients with severe recurrence (F3 to F4, cholestatic hepatitis) were treated (group C, n = 27). All patients (n = 81) underwent a liver biopsy at baseline and after follow-up; paired hepatic venous pressure gradient (HVPG) measurements were available in 51 patients. RESULTS: Thirteen (48%) patients of group B and 5 (18.5%) of group C achieved sustained virological response. Liver fibrosis progressed > or =1 stage in 40 (49%) of 81 patients: 19 (70%) of group A versus 7 (26%) of group B (P = .001) and in 14 (54%) of group C. HVPG increased (6.5 to 13 mm Hg, P < .01) in patients in whom fibrosis worsened, whereas it decreased (5 to 3.5 mm Hg, P = .017) or remained unchanged in those with fibrosis improvement or stabilization, respectively. The only variable independently associated with fibrosis improvement/stabilization was treatment (odds ratio [OR] =3.7, 95% confidence interval [CI] 1.3 to 10, P = .009). Among treated patients, alanine aminotransferase (ALT) normalization and viral clearance were independently associated with histological or hemodynamic improvement/stabilization (OR 5.3, 95% CI 1.5 to 18, P < .01; OR 7.4, 95% CI 1.4 to 38, P = .01; respectively). CONCLUSIONS: Our data demonstrate that in liver transplantation recipients, antiviral therapy slows disease progression (particularly in sustained virological responders), as shown by its effects on liver histology and on HVPG.
Assuntos
Antivirais/uso terapêutico , Hepatite C/etiologia , Hepatite C/prevenção & controle , Interferon-alfa/uso terapêutico , Transplante de Fígado/efeitos adversos , Ribavirina/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Biópsia , Darbepoetina alfa , Progressão da Doença , Relação Dose-Resposta a Droga , Eritropoetina/análogos & derivados , Eritropoetina/uso terapêutico , Feminino , Hematínicos/uso terapêutico , Hepatite C/fisiopatologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Fígado/irrigação sanguínea , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Pressão na Veia Porta/fisiologia , Proteínas Recombinantes , Ribavirina/efeitos adversos , Prevenção SecundáriaRESUMO
Early prediction of response to therapy in genotype 1 chronic hepatitis C is difficult. Two predictive models, a pretreatment scoring model (PreT-SM) and a fourth week of therapy scoring model (4w-SM) were constructed in a cohort of 104 patients from a single center (estimation cohort) and validated in a cohort of 141 patients from four independent centers (validation cohort). Individual scores were calculated using variables independently associated with sustained virological response (SVR). Baseline viral load, aspartate aminotransferase/alanine aminotransferase ratio, serum cholesterol, and a numerical score for noninvasive estimation of liver fibrosis were included in the PreT-SM; HCV RNA clearance and PreT-SM scores were included in the 4w-SM. Receiver operating characteristic analysis revealed the area under the curve in the estimation cohort and in the validation cohort to be, respectively, 0.856 and 0.847 for the PreT-SM and 0.908 and 0.907 for the 4w-SM. Low scores were associated with SVR, high scores with non-SVR. The best cutoff scores from the PreT-SM (7 and 9.70) identified, respectively, 36% of patients with SVR and 41% of those with non-SVR from the validation cohort, with high accuracy (> or =90% positive predictive value [PPV] and specificity). Similarly, cutoff scores of 3.20 and 5.60 from the 4w-SM identified, respectively, 71% of patients with SVR and 53% of those with non-SVR from the same cohort with high accuracy (PPV and specificity >92%). In conclusion, these models predicted response to therapy before or after 4 weeks of treatment in approximately 60% of genotype 1 patients and may be valuable for the management of this condition.