RESUMO
BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.
Assuntos
Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/microbiologia , Disbiose/complicações , Disbiose/imunologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/microbiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Hepatocelular/imunologia , Modelos Animais de Doenças , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Inflamação/complicações , Inflamação/microbiologia , Neoplasias Hepáticas/imunologia , Camundongos , Tempo , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
Portal hypertension is a predictor of liver-related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon-free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open-label sofosbuvir plus ribavirin at Day 1 or after a 24-week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by -1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow-up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long-term follow-up. (EudraCT 2012-002457-29).
Assuntos
Hepacivirus , Veias Hepáticas/fisiopatologia , Hepatite C/complicações , Hepatite C/virologia , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Cirrose Hepática/complicações , Cirrose Hepática/etiologia , Pressão na Veia Porta , Adulto , Idoso , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Resposta Viral Sustentada , Fatores de Tempo , Carga ViralRESUMO
BACKGROUND: New antiviral therapies for hepatitis C infection may lead to an increase in capacity to treat because of their simplicity and safety. AIMS: To determine the likely current capacity of accredited treatment centres in treating hepatitis C (HCV) patients with interferon (IFN)-free direct acting antiviral (DAA) agents in Australia. METHOD: Data were collected from 22 centres before the introduction of DAA therapy - 11 sites from the Study 1 survey and an additional 11 sites from the Study 2 survey. The sites were selected based on consensus by viral hepatitis experts, in consultation with the NSW Agency for Clinical Innovation. The services were selected as they were experienced in the delivery of IFN-based treatments and/or had knowledge about IFN-free regimens. The sites selected offered a mix of metropolitan and regional clinics, opioid substitution clinics, Aboriginal services, general practitioner-initiated, criminal justice and nurse-led services. Following the survey, the first 3 months of actual treatment uptake, since listing in March and May 2016, became available for a comparison and were subsequently analysed. RESULTS: The survey indicated that an average of 27 h would be required to treat patients with IFN-based regimens. This was reduced to an average of 9 h if IFN-free regimens were used. The average number of patients on IFN-based treatment regimens per site was 87 per year compared to 493 per site if IFN-free therapy was freely available. There is capacity in the current health system to treat five times the numbers of patients with chronic HCV in Australia. When applying a weighted ratio; the results for all centres show a 3.6-fold increase in the capacity to treat with IFN-free regimens. However, these numbers may be an underestimate based on the first 3 months of actual treatment uptake since Pharmaceutical Benefits Scheme listing in March and May 2016. CONCLUSION: Although current sites have a significant capacity to increase rapidly HCV treatment numbers, expansion of treatment settings and new models of care and training may be required to deliver HCV treatment to all HCV-infected individuals.
Assuntos
Antivirais/uso terapêutico , Atenção à Saúde/organização & administração , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Antivirais/economia , Austrália , Análise Custo-Benefício , Atenção à Saúde/estatística & dados numéricos , Quimioterapia Combinada , Hepatite C Crônica/epidemiologia , Humanos , Resultado do TratamentoRESUMO
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Isoanticorpos/imunologia , Transplante de Fígado/efeitos adversos , Aloenxertos , Humanos , Relatório de PesquisaRESUMO
In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post-liver transplant is excellent, with 1-year survival rate >90% and 5-year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child-Turcotte Pugh score ≥9 or a model for end-stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1-year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra-hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non-alcoholic fatty liver disease-associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future.
Assuntos
Doença Hepática Terminal/cirurgia , Transplante de Fígado/tendências , Seleção de Pacientes , Transplantados , Adulto , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/psicologia , Humanos , Transplante de Fígado/mortalidade , Transplante de Fígado/psicologia , Taxa de Sobrevida/tendências , Fatores de Tempo , Transplantados/psicologiaRESUMO
Acute or recurrent bleeding from ectopic varices is a potentially life-threatening condition in rare patients with extrahepatic complete portal vein thrombosis (PVT) after liver transplantation (LT). In this setting, the role of interventional radiology is very limited and surgical shunts, in particular splenorenal shunts are usually used, despite the high associated mortality. We present the first reports of the clinical use of a new minimally invasive technique, percutaneous retroperitoneal splenorenal shunt (PRESS), in two LT recipients with life-threatening variceal hemorrhage secondary to PVT. Both patients had a successful PRESS using a transplenic approach with resolution of bleeding, avoiding the need for a potentially complicated laparotomy. The PRESS procedure is a useful addition to the interventional armamentarium that can be used in cases unsuitable for surgical shunt, and refractory to endoscopic management. In the future, this technique may be an alternative to surgical shunts as the standard procedure in patients with extra-hepatic PVT, just as the transjugular intrahepatic portosystemic shunt (TIPS) procedure has become for the management of portal hypertension in the absence of PVT. Longer-term follow-up will be needed to establish the long-term success of this procedure.
Assuntos
Transplante de Fígado , Veia Porta/patologia , Derivação Esplenorrenal Cirúrgica , Trombose Venosa/patologia , Adulto , Humanos , Masculino , Adulto JovemRESUMO
Hepatocyte clone size was measured in liver samples of 21 patients in various stages of chronic hepatitis B virus (HBV) infection and from 21 to 76 years of age. Hepatocyte clones containing unique virus-cell DNA junctions formed by the integration of HBV DNA were detected using inverse nested PCR. The maximum hepatocyte clone size tended to increase with age, although there was considerable patient-to-patient variation in each age group. There was an upward trend in maximum clone size with increasing fibrosis, inflammatory activity and with seroconversion from HBV e-antigen (HBeAg)-positive to HBeAg-negative, but these differences did not reach statistical significance. Maximum hepatocyte clone size did not differ between patients with and without a coexisting hepatocellular carcinoma. Thus, large hepatocyte clones containing integrated HBV DNA were detected during all stages of chronic HBV infection. Using laser microdissection, no significant difference in clone size was observed between foci of HBV surface antigen (HBsAg)-positive and HBsAg-negative hepatocytes, suggesting that expression of HBsAg is not a significant factor in clonal expansion. Laser microdissection also revealed that hepatocytes with normal-appearing histology make up a major fraction of the cells undergoing clonal expansion. Thus, preneoplasia does not appear to be a factor in the clonal expansion detected in our assays. Computer simulations suggest that the large hepatocyte clones are not produced by random hepatocyte turnover but have an as-yet-unknown selective advantage that drives increased clonal expansion in the HBV-infected liver.
Assuntos
Proliferação de Células , Evolução Clonal , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/patologia , Hepatócitos/fisiologia , Fígado/patologia , Integração Viral , Adulto , Fatores Etários , Idoso , Carcinoma Hepatocelular/patologia , DNA Viral/genética , Feminino , Antígenos de Superfície da Hepatite B/análise , Vírus da Hepatite B/genética , Humanos , Microdissecção e Captura a Laser , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Tempo , Adulto JovemRESUMO
Population-based evidence on the relative risk of de novo cancer in liver and cardiothoracic transplant recipients is limited. A cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized incidence ratios (SIRs) were computed by cancer type, transplanted organ and recipient age. Cox regression models were used to compare cancer incidence by transplanted organ. During a median 5-year follow-up, the risk of any cancer in liver and cardiothoracic recipients was significantly elevated compared to the general population (n = 499; SIR = 2.62, 95%CI 2.40-2.86). An excess risk was observed for 16 cancer types, predominantly cancers with a viral etiology. The pattern of risk by cancer type was broadly similar for heart, lung and liver recipients, except for Merkel cell carcinoma (cardiothoracic only). Seventeen cancers (10 non-Hodgkin lymphomas), were observed in 415 pediatric recipients (SIR = 23.8, 95%CI 13.8-38.0). The adjusted hazard ratio for any cancer in all recipients was higher in heart compared to liver (1.29, 95%CI 1.03-1.63) and lung compared to liver (1.65, 95%CI 1.26-2.16). Understanding the factors responsible for the higher cancer incidence in cardiothoracic compared to liver recipients has the potential to lead to targeted cancer prevention strategies in this high-risk population.
Assuntos
Transplante de Coração , Transplante de Fígado , Transplante de Pulmão , Neoplasias/complicações , Adolescente , Adulto , Austrália/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
Evidence is sparse on the relative mortality risk posed by de novo cancers in liver and cardiothoracic transplant recipients. A retrospective cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized mortality ratios (SMRs) were computed by cancer type, transplanted organ, recipient age and sex. During a median 5-year follow-up, de novo cancer-related mortality risk in liver and cardiothoracic recipients was significantly elevated compared to the matched general population (n = 171; SMR = 2.83; 95% confidence interval [95%CI], 2.43-3.27). Excess risk was observed regardless of transplanted organ, recipient age group or sex. Non-Hodgkin lymphoma was the most common cancer-related death (n = 38; SMR = 16.6; 95%CI, 11.87-22.8). The highest relative risk was for nonmelanocytic skin cancer (n = 23; SMR = 49.6, 95%CI, 31.5-74.5), predominantly in males and in recipients of heart and lung transplants. Risk of death from de novo cancer was high in pediatric recipients (n = 5; SMR = 41.3; 95%CI, 13.4-96.5), four of the five deaths were non-Hodgkin lymphoma. De novo cancer was a leading cause of late death, particularly in heart and liver transplantation. These findings support tailored cancer prevention strategies, surveillance to promote early detection, and guidelines for managing immunosuppression once cancer occurs.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/efeitos adversos , Transplante de Fígado , Transplante de Pulmão , Neoplasias/mortalidade , Sistema de Registros , Adulto , Austrália/epidemiologia , Causas de Morte/tendências , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/induzido quimicamente , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
PURPOSE: We sought the attitudes of people with a cancer experience to using best case, worst case, and typical scenarios for survival to explain life expectancy. METHODS: Oncology clinic attendees and Breast Cancer Network Australia (BCNA) members completed a survey describing two formats for explaining life expectancy to a hypothetical patient with advanced cancer-providing either three scenarios for survival or just the median survival time. RESULTS: Characteristics of the 505 respondents from outpatient clinics (n = 251) and BCNA (n = 254) were median age of 58 years, female 74 %, and breast primary 64 %. More respondents agreed that explaining three scenarios (vs. median survival) would make sense (93 vs. 75 %), be helpful (93 vs. 69 %), convey hope (68 vs. 44 %), and reassure (60 vs. 40 %), while fewer respondents agreed that explaining three scenarios (vs. median survival) would upset people (24 vs. 36 %); all p values < 0.001. Most respondents agreed that each scenario should be presented: best case 89 %, worst case 82 %, and typical 92 %. For information about their own prognosis, 88 % preferred all three scenarios and 5 % a single estimate of the median. Respondents with higher education were more likely to agree that presenting three scenarios would be helpful (95 vs. 90 %, p = 0.05). Respondents with breast cancer were more likely to agree that explaining three scenarios would upset people (31 vs. 13 %, p < 0.001). CONCLUSIONS: Most respondents judged presentation of best case, worst case, and typical scenarios preferable and more helpful and reassuring than presentation of just the median survival time when explaining life expectancy to patients with advanced cancer.
Assuntos
Expectativa de Vida , Oncologia/métodos , Neoplasias/psicologia , Preferência do Paciente/psicologia , Revelação da Verdade , Fatores Etários , Idoso , Instituições de Assistência Ambulatorial , Neoplasias da Mama/patologia , Neoplasias da Mama/psicologia , Institutos de Câncer , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias/patologia , New South Wales , Preferência do Paciente/estatística & dados numéricos , Relações Profissional-Paciente , Prognóstico , Análise de SobrevidaRESUMO
INTRODUCTION: The aim of this study was to summarise and describe survival data from contemporary randomised trials of platinum-based adjuvant chemotherapy for patients with non-small-cell lung cancer (NSCLC). The goal was to assist clinicians to provide better estimates of survival for patients considering adjuvant chemotherapy following surgical resection for NSCLC. METHODS: Randomised trials of cisplatin-based adjuvant chemotherapy for resected NSCLC were identified. Survival rates at 1, 2, 5, 7 and 10 years and the following percentiles (scenario): 90th (worst case), 75th (lower typical), median, 25th (upper typical) and 10th (best case) were extracted from each overall survival (OS) curve. RESULTS: Thirty-eight OS curves from 19 trials (7042 patients) were analysed. With adjuvant chemotherapy, the median OS rate (interquartile range) at 1 year was 91% (85-95), 2 years was 73% (69-88), 5 years was 61% (45-65) and 7 years was 49% (38-65). With observation only, the median OS rate (interquartile range) at 1 year was 88% (83-92), 2 years was 74% (65-82), 5 years was 55% (42-58) and 7 years was 40% (34-45). In both arms, survival rates at 2, 5 and 7 years were well estimated by raising the 1-year survival rate to the power of two, five and seven respectively. Few trials reported survival rates at 10 years. CONCLUSION: Simple percentages and their powers provide a useful starting point for estimating and describing survival to patients considering adjuvant chemotherapy after surgery for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Preferência do Paciente , Taxa de Sobrevida/tendências , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Quimioterapia Adjuvante , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/tendências , Resultado do TratamentoRESUMO
BACKGROUND: Hyponatraemia in liver failure is associated with increased morbidity and mortality. Improving serum sodium in liver failure has been observed in patients receiving terlipressin. METHODS: We assessed the response of hyponatraemia in patients with liver failure to terlipressin using comparative retrospective analysis. RESULTS: Twenty-three patients received terlipressin for hyponatraemia after failed conservative management (median age 52 years (27-67), model for end-stage liver disease score 28 (16-38)). The median therapy was 7 days (1-27), with an average total dose of 25 mg (4-90) and a mean follow up of 51 days (5-1248). These patients were compared with 11 hyponatraemic patients managed conservatively during the same period with comparable age, baseline serum sodium and follow up. After 1 week of terlipressin therapy, serum sodium increased from a median of 120 (115-128) to 129 mmol/L (121-144) (P < 0.001), and at the end of terlipressin therapy, the serum sodium had increased significantly to 131 mmol/L (120-148) (P < 0.001). In comparison, in the conservatively managed group, the serum sodium did not increase significantly from the baseline of 123 (117-127) mmol/L. Adverse events occurred in 26% of patients receiving terlipressin, which predominantly pulmonary oedema. Importantly, more hyponatraemic patients treated with terlipressin (48%) were alive compared with the conservative group (18%), despite the latter having a significantly lower baseline median MELD score of 21 (16-30) (P = 0.008). Moreover, the transplant-free survival was higher in the terlipressin (30%) compared with the conservative group (0%). CONCLUSIONS: Terlipressin is effective in treating hyponatraemia in liver failure. Importantly, terlipressin use results in better transplant-free survival but also more adverse events.
Assuntos
Hiponatremia/tratamento farmacológico , Hiponatremia/epidemiologia , Falência Hepática/tratamento farmacológico , Falência Hepática/epidemiologia , Lipressina/análogos & derivados , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Hiponatremia/sangue , Falência Hepática/sangue , Lipressina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , TerlipressinaRESUMO
Human CD26 has dipeptidyl peptidase-4 (DPP IV) enzyme activity and binds to adenosine deaminase (ADA). CD26 is costimulatory for lymphocytes and has a circulating soluble form (sCD26). DPP IV enzyme inhibition is a new successful type 2 diabetes therapy. We examined whether the ADA binding and catalytic functions of sCD26 contribute to its effects on T-cell proliferation. Wildtype soluble recombinant human CD26 (srhCD26), an enzyme inactive mutant (srhCD26E-) and an ADA non-binding mutant (srhCD26A-) were co-incubated in in vitro T-cell proliferation assays with peripheral blood mononuclear cells (PBMC) stimulated with phytohaemagglutinin (PHA), muromonab-CD3 or Herpes simplex virus antigen (HSV Ag). Both srhCD26 and srhCD26E- enhanced PHA-induced T-cell proliferation dose-dependently in all six subjects tested. srhCD26 and srhCD26A- had no overall effect on anti-CD3-stimulated PBMC proliferation in four of five subjects. srhCD26, srhCD26E- and srhCD26A- enhanced HSV Ag induced PBMC proliferation in low responders to HSV Ag, but had no effect or inhibited proliferation in HSV-high responders. Thus, effects of soluble human CD26 on human T-cell proliferation are mechanistically independent of both the enzyme activity and the ADA-binding capability of sCD26.
Assuntos
Adenosina Desaminase/metabolismo , Proliferação de Células , Dipeptidil Peptidase 4/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Adulto , Células Cultivadas , Dipeptidil Peptidase 4/metabolismo , Feminino , Humanos , Ativação Linfocitária , Linfócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Solubilidade , Adulto JovemRESUMO
BACKGROUND: We aimed to describe the demand for liver transplantation (LTx) and patient outcomes on the waiting list at the Australian National Liver Transplantation Unit, Sydney over the last 20 years. METHODS: We performed a retrospective analysis with the data divided into three eras: 1985-1993, 1994-2000 and 2001-2008. RESULTS: The number of patients accepted for LTx increased from 320 to 372 and 548 (P < 0.001) with the number of LTx being performed increasing from 262 to 312 and 452 respectively (P < 0.001). The median adult recipient age increased from 45 to 48 and 52 years (P < 0.001) while it decreased in children from 4 to 2 and 1 years respectively (P = 0.001). In parallel, the deceased donor offers decreased from 1003 to 720 and 717 (P < 0.001). Methods to improve access to donor livers have been used with the use of split livers, extended criteria and non-heart beating donors, resulting in increased acceptance of deceased donor offers by 65% and 115% in the second and third eras when compared with the first era (P < 0.001). However, the adult median waiting time has increased from 23 to 41 and 120 days respectively (P < 0.001). This was associated with increased adult mortality on the waiting list from 23 to 40 and 122 respectively (P < 0.001). CONCLUSIONS: Despite the increasing proportion of donor offers being used, the waiting list mortality is increasing. A solution to this problem is an increase in organ donation to keep pace with the escalating demand for LTx.
Assuntos
Transplante de Fígado/mortalidade , Listas de Espera/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Hepatopatias/mortalidade , Hepatopatias/cirurgia , Transplante de Fígado/tendências , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos , Doadores de Tecidos , Adulto JovemRESUMO
COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.
Assuntos
Anticorpos Antivirais/biossíntese , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Pneumonia Viral/imunologia , Vacinas Virais/biossíntese , Enzima de Conversão de Angiotensina 2 , Animais , Animais Geneticamente Modificados , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/fisiologia , COVID-19 , Vacinas contra COVID-19 , Gatos , Quirópteros , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cricetulus , Feminino , Furões , Haplorrinos , Humanos , Masculino , Camundongos , Organoides/efeitos dos fármacos , Organoides/imunologia , Organoides/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , SARS-CoV-2 , Índice de Gravidade de Doença , Especificidade da Espécie , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/administração & dosagemRESUMO
BACKGROUND: The Australian Trial in Acute Hepatitis C (ATAHC) is a National Institutes of Health-funded prospective cohort study of the natural history and efficacy of treatment in individuals with recently acquired hepatitis C. Enrollment is open to both human immunodeficiency virus (HIV)-infected and -uninfected individuals. The aim of this article was to evaluate characteristics and virological outcomes among HIV-infected individuals enrolled in ATAHC. METHODS: Eligibility criteria included the first positive result of testing for anti-hepatitis C virus (HCV) antibody within 6 months and either clinical hepatitis diagnosed within the past 12 months or documented anti-HCV seroconversion within the past 24 months. RESULTS: Of the initial 103 patients enrolled, 27 (26%) were HIV infected. HIV-infected patients were more likely to be older, to have HCV genotype 1 infection and high levels of HCV RNA at baseline than were HCV-monoinfected patients. Sexual acquisition accounted for the majority (56%) of HCV infections among HIV-infected patients, compared with only 8% of HCV-monoinfected patients. The median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of pegylated interferon and ribavirin resulted in rates of undetectability of HCV RNA of 95%, 90%, and 80% at weeks 12, 24, and 48, respectively. Undetectability at week 4 was achieved in 44% of patients and yielded positive and negative predictive values for sustained virological response of 100% and 33%, respectively. CONCLUSIONS: Significant differences were demonstrated between HIV-infected and HIV-uninfected individuals enrolled in ATAHC. Treatment responses among HIV-infected individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high-risk individuals and early treatment for recently acquired HCV infection.
Assuntos
Infecções por HIV/complicações , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Adulto , Fatores Etários , Antivirais/uso terapêutico , Austrália , Estudos de Coortes , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Humanos , Interferons/uso terapêutico , Estudos Longitudinais , Masculino , Estudos Prospectivos , RNA Viral/sangue , Ribavirina/uso terapêutico , Fatores de Risco , Resultado do Tratamento , Carga ViralRESUMO
Despite advances in antiviral therapy, molecular drivers of Hepatitis C Virus (HCV)-related liver disease remain poorly characterised. Chronic infection with HCV genotypes (1 and 3) differ in presentation of liver steatosis and virological response to therapies, both to interferon and direct acting antivirals. To understand what drives these clinically important differences, liver expression profiles of patients with HCV Genotype 1 or 3 infection (n = 26 and 33), alcoholic liver disease (n = 8), and no liver disease (n = 10) were analysed using transcriptome-wide microarrays. In progressive liver disease, HCV genotype was the major contributor to altered liver gene expression with 2151 genes differentially expressed >1.5-fold between HCV Genotype 1 and 3. In contrast, only 6 genes were altered between the HCV genotypes in advanced liver disease. Induction of lipogenic, lipolytic, and interferon stimulated gene pathways were enriched in Genotype 1 injury whilst a broad range of immune-associated pathways were associated with Genotype 3 injury. The results are consistent with greater lipid turnover in HCV Genotype 1 patients. Moreover, the lower activity in inflammatory pathways associated with HCV genotype 1 is consistent with relative resistance to interferon-based therapy. This data provides a molecular framework to explain the clinical manifestations of HCV-associated liver disease.
Assuntos
Regulação Viral da Expressão Gênica/genética , Hepacivirus/genética , Hepatite C/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Fígado/virologia , Adolescente , Adulto , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Hepatopatias Alcoólicas/metabolismo , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Transcrição Gênica , Adulto JovemRESUMO
BACKGROUND: Antiviral therapy for hepatitis C has the potential to improve liver function in patients with decompensated cirrhosis. AIMS: To examine the virological response and effect of viral clearance in patients with decompensated hepatitis C cirrhosis all with MELD scores ≥15 following sofosbuvir/daclatasvir ± ribavirin. METHODS: We prospectively collected data on patients who commenced sofosbuvir/daclatasvir for 24-weeks under the Australian patient supply program (TOSCAR) and analysed outcomes including sustained viral response at 12 weeks (SVR12), death and transplant. RESULTS: 108 patients (M/F, 79/29; median age 56years; Child-Pugh 10; MELD 16; genotype 1/3, 55/47) received sofosbuvir/daclatasvir and two also received ribavirin. On intention-to-treat, the SVR12 rate was 70% (76/108). Seventy-eight patients completed 24-weeks therapy. SVR12 was achieved in 56 of these patients on per-protocol-analysis (76%). SVR12 was 80% in genotype 1 compared to 69% in genotype 3. Thirty patients failed to complete therapy. In patients achieving SVR12, median MELD and Child-Pugh fell from 16(IQR15-17) to 14(12-17) and 10(9-11) to 8(7-9), respectively (P<.001). In those who died, MELD increased from 16 to 23 at death (P=.036). Patients who required transplantation had a significantly higher baseline MELD (20) compared to those patients completing treatment (16) (P=.0010). The odds ratio for transplant in patients with baseline MELD ≥20 was 13.8(95%CI 2.78-69.04). CONCLUSIONS: SVR12 rates with sofosbuvir/daclatasvir in advanced liver disease are lower than in compensated disease. Although treatment improves MELD and Child-Pugh in most patients, a significant proportion will die or require transplantation. In those with MELD ≥20, it may be better to delay treatment until post-transplant.