RESUMO
BACKGROUND & AIMS: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis. METHODS: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD. RESULTS: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH. CONCLUSIONS: Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results.
Assuntos
Varizes Esofágicas e Gástricas , Hepatite Alcoólica , Humanos , Varizes Esofágicas e Gástricas/complicações , Hemorragia Gastrointestinal , Cirrose Hepática/complicações , Hepatite Alcoólica/complicações , FenótipoRESUMO
BACKGROUND AND AIMS: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG > 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients. APPROACH AND RESULTS: This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664-0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model's performance [C-index of 0.808 (CI95% 0.735-0.882); p =0.032]. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710-0.860), not significantly different from the HVPG-based models including or not metabolites. CONCLUSIONS: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.
Assuntos
Hipertensão Portal , Cirrose Hepática , Humanos , Hipertensão Portal/complicações , Antagonistas Adrenérgicos beta/uso terapêutico , Modelos de Riscos Proporcionais , Pressão na Veia PortaRESUMO
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.
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Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Adulto , Estudos Transversais , Fibrose , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Espanha/epidemiologiaRESUMO
Background and objective: The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain. Patients and methods: Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naïve subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018. Results: The GLE/PIB effectiveness was 100% (CI95%: 96.2100%) in the mITT population and 94.1% (CI95%: 87.597.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35±103.60 compared to 1689.42 and 2007.89 of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95 and 1689.42 of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources. Conclusions: 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.(AU)
Antecedentes y objetivo: La aparición de regímenes antivirales de acción directa altamente tolerables, eficaces y de corta duración permite simplificar el manejo de la hepatitis C, pero los costes médicos se desconocen. Así, se pretende determinar los costes médicos directos asociados a una estrategia simplificada (diagnóstico en un solo paso y monitorización reducida) para controlar la infección por VHC con un régimen de 8 semanas de glecaprevir/pibrentasvir (GLE/PIB) en la práctica clínica en España. Pacientes y métodos: Los recursos sanitarios y los datos clínicos se recopilaron retrospectivamente de las historias médicas de 101 pacientes elegibles en 11 hospitales. Los participantes fueron sujetos adultos, sin tratamiento previo de la infección por VHC y sin cirrosis, en los que se programó una estrategia combinada simplificada con GLE/PIB durante 8 semanas entre abril y noviembre de 2018. Resultados: La eficacia de GLE/PIB fue del 100% (IC 95% 96,2-100) en la población mITT y del 94,1% (IC 95% 87,5-97,8) en la población ITT. Tres sujetos suspendieron prematuramente la estrategia combinada simplificada, ninguno de ellos por razones de seguridad. Cinco sujetos reportaron 8 acontecimientos adversos de intensidad leve-moderada. Los costes directos fueron de 754,35±103,60 frente a 1.689,42 y 2.007,89 de un tratamiento teórico de 12 semanas con 4 o 5 visitas de monitorización, respectivamente; y 1.370,95 y 1.689,42 de un tratamiento teórico de 8 semanas con 3 o 4 visitas de monitorización, respectivamente. El 4,9% de los sujetos utilizaron recursos de atención médica inesperados. Conclusiones: En la vida real, el tratamiento de 8 semanas con GLE/PIB junto con una estrategia simplificada ofrece ahorros sustanciales de costos, sin afectar la eficacia y seguridad, en comparación con abordajes tradicionales.(AU)
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Humanos , Adulto , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Hepacivirus , Lactamas Macrocíclicas , Leucina/análogos & derivados , Gastroenterologia , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVE: The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain. PATIENTS AND METHODS: Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naïve subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018. RESULTS: The GLE/PIB effectiveness was 100% (CI95%: 96.2-100%) in the mITT population and 94.1% (CI95%: 87.5-97.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35±103.60 compared to 1689.42 and 2007.89 of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95 and 1689.42 of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources. CONCLUSIONS: 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.
Assuntos
Hepatite C Crônica , Hepatite C , Adulto , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis , Ciclopropanos , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Prolina/uso terapêutico , Pirrolidinas , Quinoxalinas , Estudos Retrospectivos , SulfonamidasRESUMO
BACKGROUND & AIMS: The prognosis of compensated cirrhosis is good until decompensation. In decompensated cirrhosis, bacterial infections (BIs) are common and increase the risk of death. The incidence and prognostic implications of BIs in compensated cirrhosis are less-well characterized. This study aimed to assess whether BIs influence the risk of decompensation and survival in patients with compensated cirrhosis. METHODS: This is a cohort study nested to the PREDESCI study, a double-blind, multicenter, randomized controlled trial designed to assess whether ß-blockers could prevent decompensation of cirrhosis. Patients with compensated cirrhosis and hepatic venous pressure gradient ≥10 mmHg were included. Development of BIs during follow-up was prospectively registered. Using a competing-risk time-dependent regression analysis, we investigated whether BIs affect the risk of decompensation and survival. Decompensation was defined as development of ascites, bleeding or overt encephalopathy. RESULTS: A total of 201 patients were randomized and followed for a median of 36 months (IQR 24-47 months); 34 patients (17%) developed BIs, which occurred before decompensation in 33 cases, and 29 (14%) developed ascites. Respiratory and urinary tract infections were the most frequent BIs. Decompensation occurred in 26% patients with BIs vs. 16% without BIs. Patients with BIs were at higher risk of decompensation (subdistribution hazard ratio [SHR] 2.93; 95% CI 1.02-8.42; p = 0.047) and of developing ascites (SHR 3.55; 95% CI 1.21-10.47; p = 0.022) than those without BIs. Risk of death was also higher in patients with BIs (subdistribution HR 6.93; 95% CI 2.64-18.18; p <0.001), although decompensation occurred before death in 71% of such cases. CONCLUSIONS: BIs have a marked impact on the natural history of compensated cirrhosis, significantly increasing the risk of decompensation, mainly that of ascites, and increasing the risk of death, which usually occurs after decompensation. Our results suggest that BIs may constitute a target to prevent decompensation. LAY SUMMARY: It is widely known that bacterial infections are common and increase the mortality risk in patients with decompensated cirrhosis. However, the relevance of bacterial infections in compensated cirrhosis has not been well studied. This study shows that in patients with compensated cirrhosis and clinically significant portal hypertension, bacterial infections occur as frequently as the development of ascites, which is the most frequent decompensating event. Bacterial infections increase the risk of progression to decompensation, mainly by increasing the risk of ascites, and also increase the risk of death, which usually occurs after decompensation. CLINICALTRIALS. GOV IDENTIFIER: NCT01059396.
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Infecções Bacterianas/complicações , Deterioração Clínica , Cirrose Hepática/complicações , Idoso , Ascite/etiologia , Infecções Bacterianas/fisiopatologia , Estudos de Coortes , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de RiscoRESUMO
INTRODUCTION AND AIMS: To determine the prevalence of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis (LC) due to hepatitis C virus (HCV) infection and to evaluate the impact of sustained viral response (SVR) on MHE. MATERIAL AND METHODS: We performed a prospective study using MHE screening and follow-up on patients with HCV and LC. The patients were evaluated at the beginning of treatment and 24 weeks after treatment. RESULTS: 64 patients were included. 51.6% were male, the median age was 62years, Child-Pugh classification A/B/C 93.8%/4.7%/1.6% and median MELD was 8.3. Prior hydropic decompensation was present in 11 patients. Median values of liver stiffness, as measured by transient elastography (TE) were 22.8 KPa. Indirect signs of portal hypertension (PH) were present in 53.1% of patients, with a mean of 11.9 mmHg among the ones with a measurement of the hepatic venous pressure gradient. The prevalence of MHE before treatment was 26.6%. After treatment, 98.4% of patients achieved SVR. The presence of MHE at 24weeks post-treatment had an statistically significant association with the presence of pre-treatment MHE (80% vs. 21.6%; p < 0.01), higher MELD scores at 24-weeks post-treatment (9.8 vs. 8; p = 0.02), higher Child-Pugh scores at 24-weeks post-treatment (p = 0.04), higher baseline INR levels (1.4 vs. 1.1; p < 0.001) and with the presence of indirect signs of PH (100% vs. 47.1%; p = 0.02). During follow-up, those patients without MHE at 24weeks post-treatment had a higher probability of experiencing an improvement in post-treatment TE (80.9% vs. 40%, p = 0.04). CONCLUSION: We found that SVR may lead to MHE resolution in a considerable proportion of patients, which has potential implications for disease prognosis.
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Antivirais/uso terapêutico , DNA Viral/genética , Hepacivirus/genética , Encefalopatia Hepática/virologia , Progressão da Doença , Feminino , Seguimentos , Hepacivirus/efeitos dos fármacos , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Estudos Prospectivos , Espanha/epidemiologia , Resultado do TratamentoRESUMO
INTRODUCTION AND AIMS: To determine the prevalence of minimal hepatic encephalopathy(MHE) in patients with liver cirrhosis (LC) due to hepatitis C virus (HCV) infection and to evaluate the impact of sustained viral response (SVR) on MHE. MATERIALS AND METHODS: We performed a prospective study using MHE screening and follow-up on patients with HCV and LC. The patients were evaluated at the beginning of treatment and 24 weeks after treatment. RESULTS: 64 patients were included. 51.6% were male, the median age was 62 years, Child-Pugh classification A/B/C 93.8%/4.7%/1.6% and median MELD was 8.3. Prior hydropic decompensation was present in 11 patients. Median values of liver stiffness, as measured by transient elastography (TE) were 22.8kPa. Indirect signs of portal hypertension (PH) were present in 53.1% of patients, with a mean of 11.9mmHg among the ones with a measurement of the hepatic venous pressure gradient. The prevalence of MHE before treatment was 26.6%. After treatment, 98.4% of patients achieved SVR. The presence of MHE at 24 weeks post-treatment had an statistically significant association with the presence of pre-treatment MHE (80% vs. 21.6%; p<0.01), higher MELD scores at 24-weeks post-treatment (9.8 vs. 8; p=0.02), higher Child-Pugh scores at 24-weeks post-treatment (p=0.04), higher baseline INR levels (1.4 vs. 1.1; p<0.001) and with the presence of indirect signs of PH (100% vs. 47.1%; p=0.02). During follow-up, those patients without MHE at 24 weeks post-treatment had a higher probability of experiencing an improvement in post-treatment TE (80.9% vs. 40%, p=0.04). CONCLUSION: We found that SVR may lead to MHE resolution in a considerable proportion of patients, which has potential implications for disease prognosis.
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Antivirais/administração & dosagem , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/etiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/complicações , Adulto , Fatores Etários , Idoso , Biópsia por Agulha , Progressão da Doença , Técnicas de Imagem por Elasticidade , Feminino , Seguimentos , Encefalopatia Hepática/epidemiologia , Encefalopatia Hepática/patologia , Hepatite C Crônica/patologia , Humanos , Imuno-Histoquímica , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Psicometria , Índice de Gravidade de Doença , Fatores Sexuais , Espanha , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with ß blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH. METHODS: This study on ß blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed. FINDINGS: Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the ß blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio [HR] 0·51, 95% CI 0·26-0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR=0·44, 95%CI=0·20-0·97, p=0·0297). The overall incidence of adverse events was similar in both groups. Six patients (four in the ß blockers group) had severe adverse events. INTERPRETATION: Long-term treatment with ß blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites. FUNDING: Spanish Ministries of Health and Economy.
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Antagonistas Adrenérgicos beta/administração & dosagem , Carvedilol/administração & dosagem , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Propranolol/administração & dosagem , Administração Oral , Adulto , Idoso , Ascite/prevenção & controle , Método Duplo-Cego , Feminino , Hemorragia Gastrointestinal/prevenção & controle , Encefalopatia Hepática/prevenção & controle , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/mortalidade , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The objective of this study was to determine the long-term clinical outcome and persistence of hepatitis B surface antigen (HBsAg) loss after discontinuation of treatment. BACKGROUND: The prognosis of patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs) who discontinue treatment after loss of HBsAg remains largely unknown, particularly in White patients. PATIENTS AND METHODS: We analysed a cohort of patients with CHB who discontinued NA treatment after loss of HBsAg. A total of 69 patients with hepatitis-B-e antigen-positive or hepatitis-B-e antigen-negative CHB with undetectable HBsAg during NA treatment were included after discontinuation of treatment, and followed up for a median period of 37.8 months (interquartile range: 23.8-54.6 months). RESULTS: At the end of follow-up, none of the patients showed spontaneous reappearance of HBsAg and only one patient had detectable hepatitis B virus DNA (22 IU/ml). Another patient negative for HBsAg and anti-HBs developed hepatitis B virus reactivation without elevated transaminases after treatment with corticosteroids and vincristine for dendritic cell neoplasm, 38 months after withdrawal of the antiviral treatment. Regarding clinical outcome, a patient with cirrhosis developed hepatocellular carcinoma, 6.6 years after discontinuing treatment. None of the patients had hepatic decompensation or underwent liver transplantation. CONCLUSION: HBsAg clearance after discontinuing NAs in patients with CHB is persistent and associated with good prognosis. The risk for developing hepatocellular carcinoma persists among patients with cirrhosis.
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Antivirais/administração & dosagem , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Nucleosídeos/administração & dosagem , Nucleotídeos/administração & dosagem , População Branca , Adulto , Antivirais/efeitos adversos , Biomarcadores/sangue , Esquema de Medicação , Feminino , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/etnologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/efeitos adversos , Nucleotídeos/efeitos adversos , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents. METHODS: We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents. RESULTS: Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI. CONCLUSIONS: In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
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Antivirais/administração & dosagem , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resposta Viral Sustentada , Resultado do Tratamento , Adulto JovemRESUMO
In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real-world HCV patient cohort. HEPA-C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA-C between December 2016 and May 2017, and treated with EBR/GZR with at least end-of-treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19-92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post-treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real-world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.
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Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Resposta Viral Sustentada , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Benzofuranos/efeitos adversos , Estudos de Coortes , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quinoxalinas/efeitos adversos , Sistema de Registros , Estudos Retrospectivos , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Espanha , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: The interferon-free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8-week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8-week administration of PTV/r/OBV/DSV in a real-world cohort. METHODS: We performed a multicentre observational study from Spanish Hepa-C database including patients receiving 8 weeks of PTV/r/OBV/DSV (October 2016-November 2017). Those with advanced fibrosis, with non-genotype 1b or who were treatment-experienced were excluded. RESULTS: A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n = 85) were male, median (range) age was 57 (23-86), ALT was 45 (11-494) IU/mL, viral load was 6.1 (3.3-8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0-F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention-to-treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7 weeks after EOT. CONCLUSION: Treatment with PTV/r/OBV/DSV in genotype 1b-infected treatment-naive patients with mild-moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132.
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Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/virologia , Compostos Macrocíclicos/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , 2-Naftilamina , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclopropanos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/patologia , Humanos , Lactamas Macrocíclicas , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Estudos Prospectivos , Espanha , Resposta Viral Sustentada , Uracila/uso terapêutico , Valina , Carga Viral , Adulto JovemAssuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Doença Aguda , Antivirais/administração & dosagem , Antivirais/classificação , Coinfecção , Quimioterapia Combinada , Genótipo , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/cirurgia , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/etiologia , Falência Hepática/etiologia , Falência Hepática/prevenção & controle , Transplante de Fígado , Recidiva , Insuficiência Renal/complicações , Terapia de Salvação , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0184550.].
RESUMO
BACKGROUND: Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. METHODS: PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety. RESULTS: Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events. CONCLUSION: In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis.
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Antivirais/efeitos adversos , Hepatite B/tratamento farmacológico , Leucemia/virologia , Tenofovir/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Feminino , Hepatite B/sangue , Hepatite B/complicações , Hepatite B/prevenção & controle , Vírus da Hepatite B/imunologia , Humanos , Leucemia/complicações , Leucemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Profilaxia Pós-Exposição/métodos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Testes Sorológicos , Tenofovir/administração & dosagem , Tenofovir/uso terapêuticoRESUMO
BACKGROUND AND AIMS: Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. METHODS: This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. RESULTS: Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. CONCLUSIONS: In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.
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Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Sistema de Registros , Simeprevir/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: The development of direct-acting antiviral agents (DAAs) is a major step forward in the treatment of hepatitis C (HCV). The aims of the study were to evaluate the efficacy and tolerability of DAAs in kidney transplant (KT) recipients. METHODS: Hepa-C is a Spanish registry of patients treated with DAAs in which clinical, virological and analytical data were prospectively included. We report on the data from 103 KT recipients who received DAAs. RESULTS: The most commonly used DAAs combinations were sofosbuvir/ledipasvir (n=59, 57%) and sofosbuvir+daclatasvir (n=18, 17%). Ribavirin was used in 41% of patients. Sustained viral response after 12weeks (SVR12) rate was 98%. Grade 2 or 3 anemia appeared in 14 (33%) of patients receiving ribavirin and in 9 (15%) without (p=0.03). There were three episodes of acute humoral graft rejection. No patient discontinued therapy due to adverse events. Importantly, 57 (55%) patients required immunosuppression dose adjustment. Overall, there were no statistically significant differences in the mean level of serum creatinine, eGFR and proteinuria before and after treatment. Nonetheless, seventeen (16%) patients experienced renal dysfunction (increase in serum creatinine >25%) during antiviral therapy, of whom 65% were cirrhotic in comparison with only 29% cirrhotic patients who did not develop significant renal dysfunction (p=0.004). CONCLUSIONS: Antiviral therapy with DAAs was highly efficacious and safe in KT recipients. Nevertheless, a non-negligible number of patients, most of them cirrhotic, developed mild allograft dysfunction and a significant proportion of patients required immunosuppression dose adjustment, warranting a close follow-up during therapy. LAY SUMMARY: Infection by hepatitis C virus is often found in kidney transplant patients and its presence increases mortality and graft failure. We investigated the efficacy and safety of the new direct-acting hepatitis C antivirals in this population, in which previous information is scarce. Our data shows that, as occurs in the non-transplant setting, new anti-HCV antivirals are highly efficacious kidney transplant patients. Overall, this therapy is also quite safe, although worsening of renal function is observed in 16% of patients warranting a close follow-up observation of graft function during antiviral therapy.