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1.
Dig Dis Sci ; 68(1): 291-303, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35552941

RESUMO

BACKGROUND AND AIMS: In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment. METHODS: 3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR). RESULTS: At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p < 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 > 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis. CONCLUSIONS: Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.


Assuntos
Hepatite C Crônica , Hepatite C , Humanos , Masculino , Antivirais , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Resposta Viral Sustentada , Austrália/epidemiologia , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Cirrose Hepática/complicações , Hepacivirus/genética , Resultado do Tratamento
2.
J Infect Dis ; 227(1): 123-132, 2022 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-36108079

RESUMO

BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.


Assuntos
Hepatite B Crônica , Células T Matadoras Naturais , Humanos , Vírus da Hepatite B , Receptor 2 Toll-Like , Receptor Gatilho 1 Expresso em Células Mieloides , Estudos Prospectivos , Receptores Toll-Like , Transdução de Sinais , Antivirais/uso terapêutico , Antígenos E da Hepatite B
3.
BMC Gastroenterol ; 22(1): 339, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35820850

RESUMO

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.


Assuntos
Hepatite C Crônica , Hepatite C , Adulto , Idoso , Antivirais/uso terapêutico , Austrália/epidemiologia , Seguimentos , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Programas Nacionais de Saúde , Estudos Prospectivos , Resposta Viral Sustentada
4.
Liver Transpl ; 27(7): 1007-1018, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33606328

RESUMO

Coronary artery disease (CAD) confers increased perioperative risk in patients undergoing liver transplantation (LT). Although routine screening for CAD is recommended, there are limited data on the effectiveness of screening strategies. We evaluated the safety and efficacy of a 3-tiered cardiac risk-assessment protocol that stratifies patients based on age and traditional cardiac risk factors. We peformed a single-center, prospective, observational study of consecutive adult patients undergoing LT assessment (2010-2017). Patients were stratified into low-risk (LR), intermediate-risk (IR), or high-risk (HR) cardiac groups and received standardized investigations with selective use of transthoracic echocardiography (TTE), dobutamine stress echocardiography (DSE), computed tomography coronary angiography (CTCA), and coronary angiography (CA). Primary outcomes were cardiac events (CEs) and cardiovascular death up to 30 days after LT. Overall, 569 patients were included, with 76 patients identified as LR, 256 as IR, and 237 as HR. Cardiac risk factors included diabetes mellitus (26.0%), smoking history (47.3%), hypertension (17.8%), hypercholesterolemia (7.2%), family (17.0%) or prior history of heart disease (6.0%), and obesity (27.6%). Of the patients, 42.0% had ≥2 risk factors. Overall compliance with the protocol was 90.3%. Abnormal findings on TTE, DSE, and CTCA were documented in 3, 23, and 44 patients, respectively, and 12 patients were not listed for transplantation following cardiac assessment (1 LR, 2 IR, and 9 HR). Moderate or severe CAD was identified in 25.4% of HR patients on CTCA following a normal DSE. CEs were recorded in 7 patients (1.2%), with 2 cardiovascular deaths (0.4%). Cardiac risk stratification based on traditional cardiac risk factors with the selective use of DSE, CTCA, and CA is a safe and feasible approach that results in a low perioperative cardiac event rate.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Transplante de Fígado , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/cirurgia , Dobutamina , Fatores de Risco de Doenças Cardíacas , Humanos , Transplante de Fígado/efeitos adversos , Estudos Observacionais como Assunto , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
5.
Med J Aust ; 213(10): 464-470, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33015834

RESUMO

OBJECTIVE: To assess long term graft and patient survival after donor liver retransplantation in children in Australia and New Zealand during 1986-2017; to determine the factors that influence survival. DESIGN: Retrospective cohort analysis (registry data). SETTING, PARTICIPANTS: Australia and New Zealand Liver Transplant Registry data for all liver retransplantations in children (under 18 years of age), 1986-2017, in all four paediatric and six adult liver transplantation centres in the two countries. MAIN OUTCOME MEASURES: Graft and patient survival at one, 5, 10 and 15 years. RESULTS: 142 liver retransplantations were undertaken in children (59 during 1986-2000, 83 during 2001-2017). Kaplan-Meier survival analysis indicated that survival was significantly greater during 2001-2017 than 1986-2000 (P < 0.001). During 2001-2017, graft survival one year after retransplantation was 84%, at 5 years 75%, at 10 years 70%, and at 15 years 54%; patient survival was 89% at one year, 87% at 5 years, 87% at 10 years, and 71% at 15 years. Median time between transplantations was 0.2 years (IQR, 0.03-1.4 years) during 1986-2000, and 1.8 years (IQR, 0.1-6.8 years) during 2001-2017 (P = 0.002). The proportion of graft failures that involved split grafts was larger during 2001-2017 (35 of 83, 42%) than 1986-2000 (10 of 59, 17%). Graft type, cause of graft failure, and number of transplants did not influence survival following retransplantation. CONCLUSION: Survival for children following retransplantation is excellent. Graft survival is similar for split and whole grafts. Children on the liver waiting list requiring retransplantation should have the same access to donor grafts as children requiring a first transplant.


Assuntos
Transplante de Fígado/mortalidade , Reoperação , Adulto , Austrália/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Lactente , Estimativa de Kaplan-Meier , Transplante de Fígado/métodos , Masculino , Nova Zelândia/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Doadores de Tecidos , Resultado do Tratamento , Listas de Espera
6.
J Gastroenterol Hepatol ; 35(4): 673-679, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31693755

RESUMO

BACKGROUND AND AIM: The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. METHODS: Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. RESULTS: The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). CONCLUSIONS: The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.


Assuntos
Cirrose Hepática Biliar/epidemiologia , Austrália/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Fatores de Tempo
7.
Dig Endosc ; 32(5): 761-768, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31863515

RESUMO

BACKGROUND AND AIM: Risk stratification is recommended in all patients with acute variceal bleeding (AVB). It remains unclear whether liver disease severity or upper gastrointestinal bleeding (UGIB) scoring algorithms offer superior predictive ability. We aimed to validate the AIMS65 score as a predictor of mortality in AVB, and to compare AIMS65 with established UGIB and liver disease severity risk stratification scores. METHODS: International Classification of Diseases, Tenth Revision codes identified patients presenting with AVB to three tertiary centers over a 48-month period. Patients were risk-stratified using AIMS65, Rockall, pre-endoscopy Rockall, Child-Pugh, Model for End-stage Liver Disease (MELD) and United Kingdom MELD (UKELD) scores. Primary outcomes were inpatient and 6-week mortality and inpatient rebleeding. RESULTS: Two hundred and twenty-three patients were included. Inpatient and 6-week mortality were 13.9% and 15.5% respectively. Prediction of inpatient mortality by AIMS65 (area under the receiver-operating characteristic curve [AUROC: 0.84]) was equivalent to UGIB (Rockall: 0.79, pre-Rockall: 0.78) and liver risk scores (MELD: 0.81, UKELD: 0.79, Child-Pugh: 0.78). AIMS65 score ≥3 best defined high- and low-risk groups for inpatient mortality (mortality 37.7% vs 4.9%). AIMS65 (AUROC: 0.62) was equivalent to UGIB risk scores (pre-Rockall: 0.64, Rockall: 0.70) in predicting inpatient rebleeding and superior to liver risk scores (MELD: 0.56, UKELD: 0.57, Child-Pugh: 0.60). CONCLUSIONS: AIMS65 is equivalent to established UGIB and liver disease severity risk stratification scores in predicting mortality, and superior to liver scores in predicting rebleeding.


Assuntos
Doença Hepática Terminal , Varizes Esofágicas e Gástricas , Varizes Esofágicas e Gástricas/diagnóstico , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Mortalidade Hospitalar , Humanos , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Reino Unido/epidemiologia
8.
Liver Transpl ; 25(10): 1480-1487, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31282126

RESUMO

Sarcopenia is associated with mortality in cirrhosis, but there is no gold standard for its diagnosis. The comparative utility of different diagnostic methods is unknown. This single-center observational cohort study followed 145 men referred for liver transplant evaluation between 2005 and 2012. Muscle mass was estimated by handgrip strength, dual energy X-ray absorptiometry (DEXA) lean mass, and single-slice computed tomography (CT) scan at the fourth lumbar vertebra. Recorded outcomes included time to death or liver transplantation. The median (interquartile range [IQR]) age was 54 years (47-59 years), and Model for End-Stage Liver Disease (MELD) score was 17 (14-23). Of 145 men, 56 died with a median (IQR) time to death of 7.44 months (3.48-14.16 months). In total, 79 men underwent transplantation with median (IQR) time to transplant of 7.20 months (3.96-12.84 months). The prevalence of sarcopenia differed between diagnostic modalities with 70.3% using CT muscle mass, 45.9% using handgrip strength, and 38.7% using DEXA. Muscle mass was inversely associated with wait-list mortality for measured CT muscle mass (hazard ratio [HR], 0.94; 95% confidence interval (CI), 0.90-0.98; P = 0.002), DEXA muscle mass (HR, 0.99; 95% CI, 0.99-0.99; P = 0.003), and handgrip strength (HR, 0.94; 95% CI, 0.91-0.98; P = 0.002). These results retained significance independent of the MELD score. In predicting mortality, the MELD-handgrip strength bivariate Cox model was superior to a MELD-CT muscle Cox model (P < 0.001). In conclusion, handgrip strength combined with MELD score was the superior predictive model in this novel study examining 3 commonly employed techniques to diagnose sarcopenia in cirrhosis. Handgrip strength has additional potential clinical benefits because it can be performed serially without the radiation dose, cost, and access issues attributable to CT and DEXA.


Assuntos
Doença Hepática Terminal/mortalidade , Força da Mão/fisiologia , Cirrose Hepática/mortalidade , Transplante de Fígado , Sarcopenia/diagnóstico , Absorciometria de Fóton , Progressão da Doença , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/patologia , Doença Hepática Terminal/cirurgia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Prevalência , Prognóstico , Estudos Retrospectivos , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Sarcopenia/fisiopatologia , Índice de Gravidade de Doença , Análise de Sobrevida , Tomografia Computadorizada por Raios X
9.
Liver Transpl ; 25(1): 35-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30379388

RESUMO

Acetaminophen-induced acute liver failure (ALF) may require emergency liver transplantation (LT) in the presence of specific criteria, and its management may also include intracranial pressure (ICP) monitoring in selected patients at high risk of cerebral edema. We aimed to test the hypothesis that management of such patients without ICP monitoring or LT would yield outcomes similar to those reported with conventional management. We interrogated a database of all patients treated in an intensive care unit for acetaminophen-induced ALF between November 2010 and October 2016 and obtained relevant information from electronic medical records. We studied 64 patients (58 females) with a median age of 38 years. Such patients had a high prevalence of depression, substance abuse, or other psychiatric disorders and had ingested a median acetaminophen dose of 25 g. No patient received ICP monitoring or LT. Overall, 51 (79.7%) patients survived. Of the 42 patients who met King's College Hospital (KCH) criteria, 29 (69.0%) survived without transplantation. There were 45 patients who developed severe hepatic encephalopathy, and 32 (71.1%) of these survived. Finally, compared with the KCH criteria, the current UK Registration Criteria for Super-Urgent Liver Transplantation (UKRC) for super-urgent LT had better sensitivity (92.3%) and specificity (80.4%) for hospital mortality. In conclusion, in a center applying a no ICP monitoring and no LT approach to the management of acetaminophen-induced ALF, during a 6-year period, overall survival was 79.7%, and for patients fulfilling KCH criteria, it was 69.0%, which were both higher than for equivalent patients treated with conventional management as reported in the literature. Finally, the current UKRC may be a better predictor of hospital mortality in this patient population.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Encefalopatia Hepática/epidemiologia , Falência Hepática Aguda/terapia , Adulto , Feminino , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/etiologia , Mortalidade Hospitalar , Humanos , Pressão Intracraniana , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/complicações , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Seleção de Pacientes , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
10.
Liver Transpl ; 25(11): 1620-1633, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31469227

RESUMO

Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX), which can lead to progressive liver disease characterized by recurrent EPP crises and end-stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X-linked EPP. No patient had follow-up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX-lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX-lowering treatment with the intensity adjusted to achieve a target Erc-PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.


Assuntos
Doença Hepática Terminal/terapia , Rejeição de Enxerto/epidemiologia , Transplante de Fígado , Protoporfiria Eritropoética/patologia , Transplante de Células-Tronco , Listas de Espera/mortalidade , Adolescente , Adulto , Aloenxertos/patologia , Progressão da Doença , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Feminino , Rejeição de Enxerto/patologia , Humanos , Lactente , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Protoporfiria Eritropoética/mortalidade , Protoporfiria Eritropoética/terapia , Recidiva , Sistema de Registros/estatística & dados numéricos , Transplante Homólogo , Adulto Jovem
11.
Liver Transpl ; 25(1): 25-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609187

RESUMO

The worldwide increase in obesity and diabetes has led to predictions that nonalcoholic steatohepatitis (NASH) will become the leading indication for orthotopic liver transplantation (OLT). Data supporting this prediction from outside the United States are limited. Thus, we aimed to determine trends in the frequency of NASH among adults listed and undergoing OLT in Australia and New Zealand (ANZ) from 1994 to 2017. Data from the ANZ Liver Transplant Registry were analyzed with patients listed for fulminant liver failure, retransplantation, or multivisceral transplants excluded. Nonparametric trend, Spearman rank correlation, and regression analysis were used to assess trends in etiologies of liver disease over time. Of 5016 patient wait-list registrants, a total of 3470 received an OLT. The percentage of patients with NASH activated for OLT increased significantly from 2.0% in 2003 to 10.9% in 2017 (trend analyses; P < 0.001). In 2017, NASH was the third leading cause of chronic liver disease (CLD) among wait-list registrants behind chronic hepatitis C virus (HCV; 29.5%) and alcohol (16.1%). Similarly, significant increases over time in the percentage of patients undergoing OLT were observed for HCV and NASH (all trend analyses; P < 0.001) but with significant reductions in primary sclerosing cholangitis and cryptogenic cirrhosis (both P < 0.05). By 2017, NASH was the third leading cause of liver disease among patients undergoing OLT (12.4%) and behind chronic HCV (30.2%) and alcohol (18.2%). NASH also became the third most frequent etiology of CLD in patients transplanted (13.8%) with concomitant hepatocellular carcinoma by 2017. In conclusion, NASH is increasing as a primary etiology of liver disease requiring listing and liver transplantation in ANZ.


Assuntos
Doença Hepática Terminal/cirurgia , Transplante de Fígado/tendências , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Listas de Espera , Austrália/epidemiologia , Progressão da Doença , Doença Hepática Terminal/patologia , Feminino , Humanos , Incidência , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais
12.
J Viral Hepat ; 26(2): 271-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30315682

RESUMO

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.


Assuntos
Genoma Humano , Hepatite B/complicações , Falência Hepática Aguda/genética , Falência Hepática Aguda/virologia , Transplante de Fígado/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Adulto , Exoma/genética , Feminino , Predisposição Genética para Doença , Genômica , Hepatite B/imunologia , Anticorpos Anti-Hepatite B/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sequência de DNA , Adulto Jovem
13.
Hepatology ; 68(4): 1298-1307, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29672891

RESUMO

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).


Assuntos
Benzimidazóis/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim , Transplante de Fígado , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Ácidos Aminoisobutíricos , Ciclopropanos , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Hepatite C Crônica/diagnóstico , Humanos , Internacionalidade , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prognóstico , Prolina/análogos & derivados , Pirrolidinas , Medição de Risco , Transplantados , Resultado do Tratamento
14.
Liver Int ; 39(6): 1089-1097, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30746903

RESUMO

INTRODUCTION: Reduced muscle area on CT scan is an independent predictor of mortality in cirrhosis. We examine for the first time the relationship between dual energy x-ray absorptiometry (DEXA) lean mass parameters on outcomes in cirrhotic men awaiting liver transplantation. MATERIALS AND METHODS: We retrospectively reviewed DEXA scans performed during transplant assessment between 2001 and 2016. Baseline data including the presence of ascites and MELD score were recorded. DEXA lean mass measures were adjusted for height. The primary outcome was 12-month wait-list mortality. RESULTS: Four hundred twenty men with median age 55.4 years [interquartile range 49.2; 59.4] and MELD 16 [12; 20] were studied. Median follow-up was 58.5 [28.8; 109] months. 12-month wait-list mortality was 12.4%. Appendicular lean mass was inversely associated with mortality (HR 0.78 [0.62; 0.98], P = 0.03). Lean mass of arms (HR 0.37 [0.16; 0.83], P  = 0.02) rather than legs (HR 0.77 [0.58; 1.03], P  = 0.08) was responsible for this association. Upper limb lean mass showed a significant interaction with MELD score in predicting wait-list mortality, particularly within 4 months. Total lean mass was not associated with mortality but increased in conjunction with increasing ascites (OR for ascites 1.20 [1.15; 1.25], P < 0.001 for each unit increase in MELD). CONCLUSION: Upper limb lean mass by DEXA is strongly associated with mortality in men awaiting liver transplantation. The superiority of upper limb lean mass probably relates to confounding of lower limb measures by fluid retention. This DEXA parameter represents a novel and reproducible measure of sarcopenia in cirrhosis.


Assuntos
Absorciometria de Fóton , Cirrose Hepática/mortalidade , Transplante de Fígado , Sarcopenia/mortalidade , Listas de Espera , Austrália , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de Sobrevida
15.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614491

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease-related premature illness and deaths in the world. Treatment is largely based on lifestyle modification, which is difficult to achieve in most patients. Progression of simple fatty liver or steatosis to its severe form non-alcoholic steatohepatitis (NASH) and liver fibrosis has been explained by a 'two-hit hypothesis'. Whilst simple steatosis is considered the first hit, its transformation to NASH may be driven by a second hit. Of several factors that constitute the second hit, advanced glycation end products (AGEs), which are formed when reducing-sugars react with proteins or lipids, have been implicated as major candidates that drive steatosis to NASH via the receptor for AGEs (RAGE). Both endogenous and processed food-derived (exogenous) AGEs can activate RAGE, mainly present on Kupffer cells and hepatic stellate cells, thus propagating NAFLD progression. This review focuses on the pathophysiology of NAFLD with special emphasis on the role of food-derived AGEs in NAFLD progression to NASH and liver fibrosis. Moreover, the effect of dietary manipulation to reduce AGE content in food or the therapies targeting AGE/RAGE pathway on disease progression is also discussed.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Progressão da Doença , Alimentos/efeitos adversos , Células Estreladas do Fígado/metabolismo , Humanos , Células de Kupffer/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente
16.
Hepatology ; 66(3): 989-991, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28295483

RESUMO

We report a case of dramatic systemic inflammatory symptoms and biochemical signs of inflammation related to multiple hepatic adenomas that completely resolved after cessation of the oral contraceptive pill (OCP) and associated adenoma regression. This represents a case of dramatic symptoms that resolved after estrogen withdrawal alone. (Hepatology 2017;66:989-991).


Assuntos
Adenoma de Células Hepáticas/diagnóstico por imagem , Anticoncepcionais Orais Hormonais/efeitos adversos , Estrogênios/efeitos adversos , Neoplasias Hepáticas/diagnóstico por imagem , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Adenoma de Células Hepáticas/cirurgia , Adulto , Anticoncepcionais Orais Hormonais/administração & dosagem , Estrogênios/administração & dosagem , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/cirurgia , Síndrome de Resposta Inflamatória Sistêmica/terapia , Tomografia Computadorizada por Raios X/métodos , Suspensão de Tratamento
17.
Artigo em Inglês | MEDLINE | ID: mdl-28947470

RESUMO

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0-24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.


Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Insuficiência Hepática/metabolismo , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapêutico , Adolescente , Adulto , Idoso , Amidas , Antivirais/efeitos adversos , Antivirais/farmacocinética , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Feminino , Hepacivirus/enzimologia , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/farmacocinética , Quinoxalinas/efeitos adversos , Sulfonamidas , Adulto Jovem
18.
Liver Transpl ; 23(4): 487-497, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28133934

RESUMO

Balancing immunosuppression after liver transplant is difficult, with clinical events common. We investigate whether a novel immune biomarker based on a laboratory platform with widespread availability that measures interferon γ (IFNγ) after stimulation with a lyophilized ball containing an adaptive and innate immune stimulant can predict events following transplantation. A total of 75 adult transplant recipients were prospectively monitored in a blinded, observational study; 55/75 (73.3%) patients experienced a total of 89 clinical events. Most events occurred within the first month. Low week 1 results were significantly associated with risk of early infection (area under the receiver operating characteristic curve [AUROC], 0.74; P = 0.008). IFNγ ≤ 1.30 IU/mL (likelihood ratio positive, 1.93; sensitivity, 71.4%; specificity, 63.0%) was associated with the highest risk for infection with minimal rejection risk. Nearly half the cohort (27/60, 45.0%) expressed IFNγ ≤ 1.30 IU/mL. Moreover, an elevated week 1 result was significantly associated with the risk of rejection within the first month after transplant (AUROC, 0.77; P = 0.002), but no episodes of infection. On multivariate logistic regression, IFNγ ≥ 4.49 IU/mL (odds ratio, 4.75) may be an independent predictor of rejection (P = 0.05). In conclusion, low IFNγ suggesting oversuppression is associated with infections, whereas high IFNγ indicating undersuppression is associated with rejection. This assay offers the potential to allow individualization and optimization of immunosuppression that could fundamentally alter the way patients are managed following transplantation. Liver Transplantation 23 487-497 2017 AASLD.


Assuntos
Doenças Transmissíveis/sangue , Rejeição de Enxerto/sangue , Terapia de Imunossupressão/efeitos adversos , Interferon gama/sangue , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/sangue , Medicina de Precisão/métodos , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/imunologia , Doença Hepática Terminal/cirurgia , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Terapia de Imunossupressão/métodos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/imunologia , Curva ROC , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Adulto Jovem
19.
Hepatology ; 63(5): 1430-41, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26822022

RESUMO

UNLABELLED: Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY-3+ study (N = 50) evaluated DCV-SOF with ribavirin (RBV) in treatment-naïve (n = 13) or treatment-experienced (n = 37) genotype 3-infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open-label DCV-SOF (60 + 400 mg daily) with weight-based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). SVR12 (intention-to-treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12-week group) did not enter post-treatment follow-up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment-related serious AEs. CONCLUSION: The all-oral regimen of DCV-SOF-RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3-infected patients with advanced liver disease, irrespective of past HCV treatment experience.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/classificação , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Cirrose Hepática/etiologia , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Idoso , Carbamatos , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Ribavirina/efeitos adversos , Sofosbuvir/efeitos adversos , Valina/análogos & derivados
20.
Liver Int ; 37(6): 827-835, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27896895

RESUMO

BACKGROUND: Multidrug-resistant HBV continues to be an important clinical problem. The TDF-109 study demonstrated that TDF±LAM is an effective salvage therapy through 96 weeks for LAM-resistant patients who previously failed ADV add-on or switch therapy. We evaluated the 5-year efficacy and safety outcomes in patients receiving long-term TDF±LAM in the TDF-109 study. METHODS: A total of 59 patients completed the first phase of the TDF-109 study and 54/59 were rolled over into a long-term prospective open-label study of TDF±LAM 300 mg daily. RESULTS: Results are reported at the end of year 5 of treatment. At year 5, 75% (45/59) had achieved viral suppression by intent-to-treat analysis. Per-protocol assessment revealed 83% (45/54) were HBV DNA undetectable. Nine patients remained HBV DNA detectable, however 8/9 had very low HBV DNA levels (<264IU/mL) and did not meet virological criteria for virological breakthrough (VBT). One patient experienced VBT, but this was in the setting of documented non-compliance. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Four patients discontinued TDF, one patient was lost to follow-up and one died from hepatocellular carcinoma. CONCLUSIONS: Long-term TDF treatment appears to be safe and effective in patients with prior failure of LAM and a suboptimal response to ADV therapy. These findings confirm that TDF has a high genetic barrier to resistance is active against multidrug-resistant HBV, and should be the preferred oral anti-HBV agent in CHB patients who fail treatment with LAM and ADV.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Adenina/uso terapêutico , Adulto , Austrália , DNA Viral/sangue , Farmacorresistência Viral , Feminino , Vírus da Hepatite B , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Terapia de Salvação , Resultado do Tratamento , Carga Viral
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